Compounds comprising a naphthyridine or pyridopyrimidine core as PTC read-through agents

Abstract

Disclosed are compounds of the formula (I), or a tautomeric form thereof, or a pharmaceutically acceptable salt or N-oxide thereof: (I) wherein R1, R2a, R2b, R3, R4, R5, and X are as defined herein. Compounds of the invention may be suitable for use in treating diseases / conditions which are associated with PTC mutations. Also disclosed are pharmaceutical compositions comprising the compounds; and the compounds for use in treating conditions or disorders which are associated with PTC mutations in a subject.

Description

Compounds Comprising a Naphthyridine or Pyrido-Pyridine Core

[0001] This invention relates to compounds comprising a pyridine-containing polycyclic core having pharmacological activity, processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of various disorders. BACKGROUND

[0002] When a ribosome encounters a termination sequence during the process of messenger RNA (mRNA) translation no cognate transfer RNA (tRNA) can bind. This leads to a halt in protein production, release factor (RF) proteins binding to the empty site on the ribosome and conformational changes in the ribosome that lead to the break-up of the ribosomal complex. Although accurate, translational termination is not 100% effective and its efficiency depends on competition between the recognition of the stop codon by eRF1, and the decoding of the stop codon by a near-cognate tRNA (i.e. a natural suppressor tRNA). The latter case leads to the suppression of translation termination, also called “read-through”, where an amino acid is incorporated in place of the stop (Dabrowski, M. et al., RNA Biology 2015, 12, 950-958).

[0003] If the terminating codon occurs before the full length protein is made then the termination codon is a “premature” termination codon (PTC) and the truncated protein may not be functional. Normal terminating stop codons are usually in a genetic and structural context that reinforces their effectiveness and are usually more resistant to read-through than PTCs arising through truncating mutations (Wangen and Green, 2020 Elife 9:e52611).

[0004] Over 1800 separate inherited genetic disorders have been identified where the causative mutation in a proportion of individuals is a nonsense mutation where an in-frame, premature termination codon (PTC) leads to a loss of gene function (Kellermayer, R. European Journal of  Medical  Genetics  2006, 49,  445-450). Over 9,600 PTC mutations have been published, representing around 10% of all reported gene mutations (Krawczak, M. et al., Human Mutation 2000, 15, 45-51, Mort, M. et al., Human Mutation 2008, 29, 1037-1047).

[0005] Nonsense mutations are involved in the pathology of a range of disorders; from polygenic pathologies such as cancer to monogenic diseases such as cystic fibrosis and Duchenne muscular dystrophy for which a PTC accounts for around 10% or 5-10% of all cases respectively (Keeling, K.M. & Bedwell, D.M., Journal of Molecular Medicine 2002, 80, 367-376, Kellermayer, R. European Journal of Medical Genetics 2006, 49, 445-450).

[0006] Whereas monogenetic diseases arise from either an inherited or de novo germline mutation resulting in a PTC in, for example cancer, somatic mutations can give rise to PTC mutations in tumour suppressor genes, for example.

[0007] One of the surveillance systems used by the cell to remove abnormal mRNA transcripts that prematurely terminate translation is the nonsense mediated decay (NMD) pathway. It targets mRNA containing a PTC sequence more than ~50 base pairs upstream from the penultimate exon-exon junction (Maquat, L.E., Nature Reviews, Molecular Cell biology 2004, 5, 89-99).

[0008] The combination of premature termination of protein production and NMD of mRNA containing PTCs, can lead to almost total loss of protein production for mutant genes encoding a PTC.

[0009] Mechanisms by which translational read-though of PTC mutations may be achieved include but are not limited to: reducing the translational fidelity of the ribosome; reducing the efficiency of the translational termination machinery; inhibiting NMD; interfering with the regulation of gene transcription or translation or stabilising mRNA against NMD (Kellermayer, R European Journal of Medical Genetics 2006, 49, 445-450, Belgrader, P. J. C., and Maquat, L.E., Proc. Natl. Acad. Sci. USA 1993, 90, 482-486).

[0010] Agents which allow translational read-through of PTC mutations have the potential to treat any disease where the presence of a PTC in a gene is directly causative, a risk factor or an aggravating factor in disease.

[0011] Aminoglycosides (such as paromomycin, gentamicin, G418 / geneticin) are a class of antibiotics able to reduce translational fidelity. They exert their antibacterial action through inhibition of prokaryotic protein synthesis, however, at sub-lethal doses they lower translational fidelity of mammalian ribosomes leading to an increased rate of mis-incorporation of amino acids and also to an increased rate of translational read-through of stop codons (Davies, J. & Gorini, L., Proc. Natl. Acad. Sci. USA 1964, 51, 883-8, Weinstein, Proc. Natl. Acad. Sci. USA 1964, 52, 988-996).

[0012] Aminoglycosides have been shown to allow read-through of PTC mutations in the CFTR gene responsible for cystic fibrosis in vitro (Bedwell, D.M., et al., Nature Medicine 1997, 3, 1280-1284) and in vivo, including patients (Ming Du, et al., Journal of Molecular Medicine 2002, 80, 595-604, Clancy, J.P. et al., Am J Respir Crit Care Med 2001, 163, 1683-1692, Wilschanski, M., et al., The New England Journal of Medicine 2003, 139, 1433-1441).

[0013] In an animal model of Duchenne muscular dystrophy (DMD), 7 of 8 male mdx mice treated with 34 mg / kg gentamicin showed increased protection from contractile injury and 10-20% restoration of wild-type dystrophin levels (Barton-Davis, E.R., et al., Journal of Clinical Investigation 1999, 104, 375-381).

[0014] Gentamicin treatment induced functional type VII collagen in recessive dystrophic epidermolysis bullosa patients (Woodley, D. T. et al. Journal of Clinical Investigation 2017, 127, 3028-3038) with in vitro evidence supporting a read-through mechanism (Has, C. et al. Journal of Investigative Dermatology 2022, 142, 1227-1230).

[0015] The read-through of genes containing PTC mutations relevant to cystinosis, Hurler syndrome, inherited blindness and cancer genes have all been demonstrated following aminoglycoside treatment (Helip-Wooley, A., et al., Molecular Genetics and Metabolism 2002, 75, 128-133, Keeling, K.M., et al., Human Molecular Genetics 2001, 10, 291-299, Moosajee, M.K., et al., Human Molecular Genetics 2008, 17, 3987-4000). However, aminoglycosides are not suitable as PTC read-through agents due to the severe toxicity observed with high doses or repeated treatments

[0016] WO2019241633 describes compositions and methods for suppressing nonsense mutations, including the compound triamterene.

[0017] Hurlbert, B. S. et al. Journal of Medicinal Chemistry (1968), 11(4), 711-17 describes 2,4-diaminopyrido[2,3-d]-pyrimidines, including pyrido[2,3-d]pyrimidine-2,4-diamine, with antibacterial and antiprotozoal effects.

[0018] Certain compounds of the present invention are suitable for use in treating diseases / conditions which are associated with PTC mutations.

[0019] A structurally novel class of compounds has now been found which provides PTC read-through agents. BRIEF SUMMARY OF THE DISCLOSURE

[0020] In accordance with a first aspect, the present invention provides a compound of formula (I), or a tautomeric form thereof, or a pharmaceutically acceptable salt or N-oxide thereof:I)wherein X is N or CR6; R1is independently selected from C0-C6-alkylene-R1a, and C2-C6-alkylene-R1b; R1ais independently selected from C3-C8cycloalkyl, C5-C8 cycloalkenyl, 3- to 10-membered heterocycloalkyl, and 5- to 10-membered heterocycloalkenyl; wherein R1ais optionally substituted with C0-C6-alkylene-R9aand / or from 1 to 6 R9groups; wherein where R1ais heterocycloalkyl or heterocycloalkenyl, the heterocycloalkyl or heterocycloalkenyl is optionally fused to a phenyl ring, wherein the phenyl ring is optionally substituted with from 1 to 4 R10groups; R1bis independently selected from NR7aR8aand OR7; wherein R1comprises at least one nitrogen atom; R2ais independently at each occurrence selected from H and C1-C4alkyl; R2bis independently at each occurrence selected from H, C1-C4alkyl, C1-C4-haloalkyl, C0-C4 alkyl-R2c, C2-C4-alkylene-R2d, C(O)-C1-C4-alkyl, S(O)-C1-C4-alkyl, and S(O)2-C1-C4-alkyl; R2cis independently selected from C3-C8cycloalkyl, C5-C8cycloalkenyl, phenyl, 3- to 8- membered heterocycloalkyl, 5- to 8-membered heterocycloalkenyl and 5-, or 6-membered heteroaryl; wherein where R2cis cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, R2cis optionally substituted with from 1 to 4 R9groups; and where R2cis phenyl, or heteroaryl, R5cis optionally substituted with from 1 to 5 R10groups; R2dis independently selected from NR7R8and OR7; or R2aand R2b, together with the nitrogen atom to which they are attached, form a 5- to 8-membered heterocycloalkyl ring; optionally substituted with 1 to 4 R9groups; R3is independently selected from H, cyano, C1-C4-alkylene-NR7R8, NR7R8, C1-C4-alkylene- OR7, OR7, SR7, SOR7, S(O)2R7, S(O)2NR7R7, CO2R7, C(O)R7, C(O)NR7R7, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, NR7-C0-C4-alkylene-R3c, O-C0-C4-alkylene-R3c, and C0-C4-alkylene-R3c; R3cis independently selected from C3-C8cycloalkyl, C5-C8cycloalkenyl, phenyl, 3- to 10- membered heterocycloalkyl, 5- to 10-membered heterocycloalkenyl and 5-, or 6-membered heteroaryl; wherein where R3cis cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, R3cis optionally substituted with from 1 to 4 R9groups; and where R3cis phenyl or heteroaryl, R3cis optionally substituted with from 1 to 5 R10groups; R4is independently selected from H, halo, cyano, NR7bR8, OR7, SR7, SOR7, S(O)2R7, S(O)2NR7R7, CO2R7, C(O)R7, C(O)NR7R7, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4- haloalkyl, O-C0-C4-alkylene-R4c, and C0-C4-alkylene-R4c; R4cis independently selected from C3-C8cycloalkyl, C5-C8cycloalkenyl, 3- to 10-membered heterocycloalkyl, 5- to 10-membered heterocycloalkenyl and 5-membered heteroaryl; wherein where R4cis cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, R4cis optionally substituted with from 1 to 4 R9groups; and where R4cis heteroaryl, R4cis optionally substituted with from 1 to 5 R10groups; R5is independently selected from H, halo, cyano, C1-C4-alkylene-NR7R8, NR7bR8, C1-C4- alkylene-OR7, OR7b, SR7, SOR7, S(O)2R7, S(O)2NR7R7, CO2R7, C(O)R7, C(O)NR7R7, C1-C4- alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, NR7-C0-C4-alkylene-R5c, O-C0-C4- alkylene-R5c, and C0-C4-alkylene-R5c; R5cis independently selected from C3-C8cycloalkyl, C5-C8 cycloalkenyl, phenyl, 3- to 10- membered heterocycloalkyl, 5- to 10-membered heterocycloalkenyl and 5-, or 6-membered heteroaryl; wherein where R5cis cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, R5cis optionally substituted with from 1 to 4 R9groups; and where R5cis phenyl or heteroaryl, R5cis optionally substituted with from 1 to 5 R10groups; or R3and R4together with the carbon atoms to which they are attached form a ring selected from: phenyl, C5-C7-cycloalkyl, 5- to 7-membered heterocycloalkyl and 5- or 6- membered heteroaryl; wherein where the ring is cycloalkyl or heterocycloalkyl, it is optionally substituted with from 1 to 6 R9groups and where the ring is phenyl or heteroaryl, it is optionally substituted with from 1 to 4 R10groups; or R4and R5together with the carbon atoms to which they are attached form a ring selected from: phenyl, C5-C7-cycloalkyl, 5- to 7-membered heterocycloalkyl and 5- or 6- membered heteroaryl; wherein where the ring is cycloalkyl or heterocycloalkyl, it is optionally substituted with from 1 to 6 R9groups and where the ring is phenyl or heteroaryl, it is optionally substituted with from 1 to 4 R10groups;R6is independently selected from H, halo, C1-C6-alkyl, and C1-C6-haloalkyl; R7and R7aare each independently at each occurrence selected from H and C1-C4alkyl; R7bis independently at each occurrence selected from C1-C4alkyl; R8is independently at each occurrence selected from H, C1-C4alkyl, C1-C4-haloalkyl and C(O)-C1-C4-alkyl R8ais independently at each occurrence selected from H, C1-C4alkyl, C1-C4-haloalkyl, C(O)- C1-C4-alkyl and phenyl optionally substituted with from 1 to 5 R10groups; or R7aand R8a, together with the nitrogen atom to which they are attached, form a 5- to 8-membered heterocycloalkyl ring; optionally substituted with 1 to 4 R9groups; R9is independently at each occurrence selected from =O, =S, halo, nitro, cyano, NR7R8, OR7, SR7, SOR7, S(O)2R7, SO2NR7R7, CO2R7, C(O)R7, CONR7R7, C1-C4-alkyl, C2-C4-alkenyl, C2- C4-alkynyl, C1-C4-haloalkyl, C1-C3-alkylene-OR7, and C1-C3-alkylene-NR7R8; R9ais independently at each occurrence selected from C3-C8cycloalkyl, C5-C8cycloalkenyl, phenyl, 3- to 8-membered heterocycloalkyl, 5- to 8-membered heterocycloalkenyl and 5-, or 6-membered heteroaryl; wherein where R9ais cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, R9ais optionally substituted with from 1 to 4 R9groups; and where R9ais phenyl, or heteroaryl, R9ais optionally substituted with from 1 to 5 R10groups; R10is independently at each occurrence selected from halo, nitro, cyano, NR7R8, OR7, SR7, SOR7, S(O)2R7, SO2NR7R7, CO2R7, C(O)R7, CONR7R7, C1-C4-alkyl, C2-C4-alkenyl, C2-C4- alkynyl, C1-C4-haloalkyl, C3-C6-cycloalkyl, C1-C3-alkylene-NR7R8, and C1-C3-alkylene-OR7; and wherein any of the aforementioned alkyl, alkylene, alkenyl, or cycloalkyl groups is optionally substituted, where chemically possible, by 1 to 5 substituents which are each independently at each occurrence selected from the group consisting of: C1-C4-alkyl, oxo, halo, nitro, cyano, NRaRb, ORa, SRa, CO2Ra, C(O)Ra, CONRaRa, S(O)Ra, and S(O)2Ra; wherein Rais independently at each occurrence selected from H, and C1-C4-alkyl; and Rbis independently at each occurrence selected from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and S(O)2-C1-C4-alkyl.

[0021] It may be that R2ais independently at each occurrence selected from H and C1-C4alkyl; and R2bis independently at each occurrence selected from H, C1-C4alkyl, C1-C4- haloalkyl, C0-C4 alkyl-R2c, C2-C4-alkylene-R2d, C(O)-C1-C4-alkyl, S(O)-C1-C4-alkyl, and S(O)2- C1-C4-alkyl.

[0022] Compounds according to formula (I) may be able to tautomerise, depending on the identity of the substituent groups, to give alternative tautomeric forms of the compounddepicted above. It may be that compounds of formula (I) are a mixture of these tautomeric forms. Said tautomeric forms may be interconverting in any given sample. The relative proportion of tautomeric forms in a given sample will be determined by the position of an equilibrium between those tautomeric forms under the conditions. The position of the equilibrium, and therefore the extent to which each tautomeric form of the compound is present, may be determined by factors including, but not limited to, identity of the substituent groups, temperature, pH, and / or the solvent (where compound of formula (I) is in solution).

[0023] In an embodiment, the compound of formula (I) is a compound of formula (II):I) wherein R1, R2a, R2b, R3, R4and R5are as defined above for formula (I).

[0024] In an embodiment, the compound of formula (I) is a compound of formula (III):( I) wherein R1, R3, R4and R5are as defined above for formula (I).

[0025] In an embodiment, the compound of formula (I) is a compound of formula (IV): R R(IV)wherein Ring A is independently selected from C3-C8cycloalkyl, C5-C8cycloalkenyl, 3- to 10- membered heterocycloalkyl, and 5- to 10-membered heterocycloalkenyl; wherein Ring A is optionally substituted with C0-C6-alkylene-R9aand / or from 1 to 6 R9groups; wherein where Ring A is heterocycloalkyl or heterocycloalkenyl, the heterocycloalkyl or heterocycloalkenyl is optionally fused to a phenyl ring, wherein the phenyl ring is optionally substituted with from 1 to 4 R10groups; and p is selected from 0, 1, 2, or 3; and wherein X, R1, R2a, R2b, R3, R4, R5, R9, R9a, and R10are as defined above for formula (I); optionally wherein X, R1, R2a, R2b, R3, R4and R5are as defined above for formula (I); and wherein Ring A is independently selected from C3-C8cycloalkyl, C5-C8cycloalkenyl, 3- to 10-membered heterocycloalkyl, and 5- to 10-membered heterocycloalkenyl; wherein Ring A is optionally substituted with from 1 to 4 R9groups; wherein where Ring A is heterocycloalkyl or heterocycloalkenyl, the heterocycloalkyl or heterocycloalkenyl is optionally fused to a phenyl ring, wherein the phenyl ring is optionally substituted with from 1 to 4 R10groups; and p is selected from 0, 1, 2, or 3.

[0026] In an embodiment, the compound of formula (I) is a compound of formula (V):(V) wherein Ring A is independently selected from C3-C8cycloalkyl, C5-C8cycloalkenyl, 3- to 10- membered heterocycloalkyl, and 5- to 10-membered heterocycloalkenyl; wherein Ring A is optionally substituted with C0-C6-alkylene-R9aand / or from 1 to 6 R9groups; wherein where Ring A is heterocycloalkyl or heterocycloalkenyl, the heterocycloalkyl or heterocycloalkenyl is optionally fused to a phenyl ring, wherein the phenyl ring is optionally substituted with from 1 to 4 R10groups; and p is selected from 0, 1, 2, or 3; and wherein X, R1, R2a, R2b, R3, R4, R5, R9, R9a, and R10are as defined above for formula (I); optionally wherein X, R1, R2a, R2b, R3, R4and R5are as defined above for formula (I); and wherein Ring A is independently selected from C3-C8cycloalkyl, C5-C8 cycloalkenyl, 3- to 10-membered heterocycloalkyl, and 5- to 10-membered heterocycloalkenyl; wherein Ring A is optionally substituted with from 1 to 4 R9groups; wherein where Ring A is heterocycloalkyl or heterocycloalkenyl, the heterocycloalkyl or heterocycloalkenyl is optionally fused to aphenyl ring, wherein the phenyl ring is optionally substituted with from 1 to 4 R10groups; and p is selected from 0, 1, 2, or 3.

[0027] In an embodiment, the compound of formula (I) is a compound of formula (VI): I)wherein X, R1, R2a, R2b, and R5are as defined above for formula (I); and wherein Ring B is independently selected from phenyl, C5-C7-cycloalkyl, 5- to 7-membered heterocycloalkyl and 5- or 6-membered heteroaryl; wherein where Ring B is cycloalkyl or heterocycloalkyl, it is optionally substituted with from 1 to 6 R9groups and where Ring B is phenyl or heteroaryl, it is optionally substituted with from 1 to 4 R10groups; optionally wherein where Ring B is cycloalkyl or heterocycloalkyl, it is optionally substituted with from 1 to 4 R9groups and where Ring B is phenyl or heteroaryl, it is optionally substituted with from 1 to 4 R10groups.

[0028] In an embodiment, the compound of formula (I) is a compound of formula (VII):(VII) wherein X, R1, R3, R2a, and R2bare as defined above for formula (I); and wherein Ring C is independently selected from phenyl, C5-C7-cycloalkyl, 5- to 7-membered heterocycloalkyl and 5- or 6-membered heteroaryl; wherein where Ring C is cycloalkyl or heterocycloalkyl, it is optionally substituted with from 1 to 6 R9groups and where Ring C is phenyl or heteroaryl, it is optionally substituted with from 1 to 4 R10groups; optionally wherein where Ring C is cycloalkyl or heterocycloalkyl, it is optionally substituted with from 1 to 6 R9groups and where Ring C is phenyl or heteroaryl, it is optionally substituted with from 1 to 4 R10groups.

[0029] The following embodiments apply to compounds of any of formulae (I)-(VII). These embodiments are independent and interchangeable. Any one embodiment may be combined with any other embodiment, where chemically allowed. In other words, any of the features described in the following embodiments may (where chemically allowable) may be combined with the features described in one or more other embodiments. In particular, where a compound is exemplified or illustrated in this specification, any two or more of the embodiments listed below, expressed at any level of generality, which encompass that compound may be combined to provide a further embodiment which forms part of the present disclosure.

[0030] R1may be C2-C6-alkylene-R1b. R1bmay be NR7aR8a. R7amay be selected from H and C1-C4-alkyl. R7amay be C1-C4-alkyl. R8amay be selected from H, C1-C4alkyl and phenyl optionally substituted with from 1 to 5 R10groups. R8amay be selected from H and C1-C4- alkyl. R8amay be C1-C4-alkyl. It may be that R7aand R8a, together with the nitrogen atom to which they are attached, form a 5- to 8-membered heterocycloalkyl ring; optionally substituted with 1 to 4 R9groups.

[0031] R1may be C0-C6-alkylene-R1a. R1may be R1a. R1may be C1-C6-alkylene-R1a.

[0032] R1amay be selected from C3-C8cycloalkyl, C5-C8 cycloalkenyl, 3- to 10-membered heterocycloalkyl, and 5- to 10-membered heterocycloalkenyl.

[0033] R1amay be 3- to 10-membered heterocycloalkyl. R1amay be a 3- to 10-membered heterocycloalkyl group having a nitrogen in the ring system, e.g. pyrrolidine. R1amay be a 3- to 10-membered heterocycloalkyl group having an amine nitrogen in the ring system. Where R1ais a 3- to 10-membered heterocycloalkyl group having an amine nitrogen in the ring system, it may be that it is attached to the rest of the molecule via a carbon atom in the ring system. Where R1ais a 3- to 10-membered heterocycloalkyl group having an amine nitrogen in the ring system, it may be that it is attached to the rest of the molecule via the nitrogen atom in the ring system. R1amay be a monocyclic 3- to 7-membered heterocycloalkyl. R1amay be a piperidine, e.g. a piperidin-4-yl. R1amay be a morpholine. R1amay be a azepane. R1amay be a pyrrolidine. R1amay be a bicyclic 7- to 10-membered heterocycloalkyl. In these embodiments, R1amay be substituted with from 1 to 6 R9groups.

[0034] It may be that R1isR9bis independently selected from H, SOR7, S(O)2R7, SO2NR7R7, CO2R7, C(O)R7, CONR7R7, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C2-C3-alkylene-OR7, and C2-C3- alkylene-NR7R8; R9cis independently at each occurrence selected from =O, =S, halo, nitro, cyano, NR7R8, OR7, SR7, SOR7, S(O)2R7, SO2NR7R7, CO2R7, C(O)R7, CONR7R7, C1-C4-alkyl, C2-C4-alkenyl, C2- C4-alkynyl, C1-C4-haloalkyl, C1-C3-alkylene-OR7, and C1-C3-alkylene-NR7R8; and m is an integer from 0 to 5.

[0035] It may be that R1isR9bis independently selected from H, SOR7, S(O)2R7, SO2NR7R7, CO2R7, C(O)R7, CONR7R7, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C2-C3-alkylene- OR7, and C2-C3- alkylene-NR7R8; R9cis independently selected from =O, =S, halo, nitro, cyano, NR7R8, OR7, SR7, SOR7, S(O)2R7, SO2NR7R7, CO2R7, C(O)R7, CONR7R7, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1- C4-haloalkyl, C1-C3-alkylene-OR7, and C1-C3-alkylene-NR7R8.

[0036] It may be that R1is, wherein: q is an integer from 0 to 6; and R9and R9aare as defined herein.

[0037] It may be that R1is , wherein:q is an integer from 0 to 6; R9is as defined herein; and R9ais independently selected from phenyl and 5-, or 6-membered heteroaryl, wherein R9ais optionally substituted with from 1 to 5 R10groups.

[0038] It may be that R1isq is an integer from 0 to 6; r is an integer from 0 to 5; and R9and R10are as defined herein.

[0039] It may be that R9bis independently selected from H, C1-C4-alkyl, and C1-C4-haloalkyl. It may be that R9bis independently selected from H and C1-C4-alkyl. It may be that R9bis independently H. It may be that R9bis independently methyl.

[0040] It may be that m is 0. It may be that m is 1. It may be that m is 2.

[0041] It may be that R9cis independently selected from halo, nitro, cyano, NR7R8, OR7, SR7, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C1-C3-alkylene-OR7, and C1-C3- alkylene-NR7R8.

[0042] It may be that R9cis independently selected from NR7R8, OR7, C1-C4-alkyl, C1-C4- haloalkyl, C1-C3-alkylene-OR7, and C1-C3-alkylene-NR7R8. It may be that R9cis independently selected from OR7and C1-C4-alkyl. It may be that R9cis methyl. It may be that R9cis OH.

[0043] R1amay be a 3- to 10-membered heterocycloalkyl wherein the heterocycloalkyl is fused to a phenyl ring. R1amay be a 3- to 6-membered heterocycloalkyl wherein theheterocycloalkyl is fused to a phenyl ring. R1amay be a 5- membered heterocycloalkyl wherein the heterocycloalkyl is fused to a phenyl ring. It may be that R1ais bicyclic when the heterocycloalkyl is fused to a phenyl ring. It may be that the phenyl ring is substituted with from 1 to 4 R10groups.

[0044] R1amay be a 5- to 10-membered heterocycloalkenyl wherein the heterocycloalkenyl is fused to a phenyl ring. R1amay be a 5- or 6-membered heterocycloalkenyl wherein the heterocycloalkenyl is fused to a phenyl ring. It may be that R1ais bicyclic when the heterocycloalkenyl is fused to a phenyl ring. It may be that the phenyl ring is substituted with from 1 to 4 R10groups.

[0045] It may be that R1ais selected from a C3-C6-cycloalkyl group or a 3- to 10– membered heterocycloalkyl group that does not contain a nitrogen in the ring system and R1ais substituted with at least one NR7R8group.

[0046] It may be that R1contains 1, 2, or 3 nitrogen atoms. It may be that R1contains a single nitrogen atom. It may be that R1contains 2 nitrogen atoms. Where R1contains 2 or 3 nitrogen atoms, at least one of the nitrogen atoms is an amine nitrogen. It may be that R1comprises 1, 2, or 3 amine nitrogen atoms, optionally a single amine nitrogen.

[0047] Ring A may be 3- to 10-membered heterocycloalkyl. Ring A may be a 3- to 10- membered heterocycloalkyl group having a nitrogen in the ring system, e.g. pyrrolidine. Ring A may be a 3- to 10-membered heterocycloalkyl group having an amine nitrogen in the ring system. Where Ring A is a 3- to 10-membered heterocycloalkyl group having an amine nitrogen in the ring system, it may be that it is attached to the rest of the molecule via a carbon atom in the ring system. Where Ring A is a 3- to 10-membered heterocycloalkyl group having an amine nitrogen in the ring system, it may be that it is attached to the rest of the molecule via the nitrogen atom in the ring system. Ring A may be a monocyclic 3- to 7-membered heterocycloalkyl. Ring A may be a piperidine, e.g. a piperidin-4-yl. Ring A may be a morpholine. Ring A may be a azepane. Ring A may be a pyrrolidine. Ring A may be a bicyclic 7- to 10-membered heterocycloalkyl. p may be 0. p may be 1. p may be 2. p may be 3.

[0048] It may be that Ring A is selected from a C3-C6-cycloalkyl group or a 3- to 10– membered heterocycloalkyl group that does not contain a nitrogen in the ring system and Ring A is substituted with at least one NR7R8group.

[0049] Ring A may be a 3- to 10-membered heterocycloalkyl wherein the heterocycloalkyl is fused to a phenyl ring. Ring A may be a 3- to 6-membered heterocycloalkyl wherein the heterocycloalkyl is fused to a phenyl ring. Ring A may be a 5- membered heterocycloalkylwherein the heterocycloalkyl is fused to a phenyl ring. Ring A fused to a phenyl ring may be a bicyclic ring system. It may be that the phenyl ring is substituted with from 1 to 4 R10groups.

[0050] Ring A may be a 5- to 10-membered heterocycloalkenyl wherein the heterocycloalkenyl is fused to a phenyl ring. Ring A may be a 5- or 6-membered heterocycloalkenyl wherein the heterocycloalkenyl is fused to a phenyl ring. Ring A fused to a phenyl ring may be a bicyclic ring system. It may be that the phenyl ring is substituted with from 1 to 4 R10groups.

[0051] It may be that R1comprises at least one amine nitrogen. An amine nitrogen is a nitrogen in an amine group. For the avoidance of doubt, the term “amine” as used herein encompasses primary amines, e.g., methylamine; secondary amines, e.g., dimethylamine; tertiary amines, e.g., trimethylamine; cyclic amines, e.g., piperidine. For the avoidance of doubt, the term “amine” as used herein excludes amides (including lactams) and sulfonamides (including cyclic sulfonamides).

[0052] R2amay be independently selected from H and C1-C2alkyl. R2amay be H.

[0053] R2bmay be independently selected from H, C1-C4alkyl, C1-C4-haloalkyl, C0-C4 alkyl- R2cand C2-C4-alkylene-R2d. R2bmay be independently selected from H, C1-C4alkyl, and C0- C4 alkyl-R2c. R2bmay be independently selected from H, and C1-C4alkyl. R2bmay be independently selected from H, and C1-C2 alkyl. R2bmay be H.

[0054] R2bmay be C2-C4-alkylene-R2d. R2dmay be NR7R8. R2dmay be OR7.

[0055] It may be that at least one of R2aand R2bis H. It may be that R2ais H and R2bis selected from H and methyl. It may be that R2ais H and R2bis methyl. It may be that R2aand R2bare each H.

[0056] X may be N. X may be CR6, e.g. CH.

[0057] R3may be H. R3may be C1-C4-alkyl, e.g. methyl.

[0058] It may be that R4is independently selected from H, halo, cyano, OR7, SR7, SOR7, S(O)2R7, S(O)2NR7R7, CO2R7, C(O)R7, C(O)NR7R7, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, O-C0-C4-alkylene-R4c, and C0-C4-alkylene-R4c.

[0059] R4may be H. R4may be C1-C4-alkyl, e.g. methyl.

[0060] It may be that R4is C0-alkylene-R4c, i.e., R4is R4c.

[0061] It may be that R4cis independently selected from C3-C8cycloalkyl, C5-C8 cycloalkenyl, 3- to 10-membered heterocycloalkyl, and 5- to 10-membered heterocycloalkenyl; wherein R4cis optionally substituted with from 1 to 4 R9groups.

[0062] R3and R4together with the carbon atoms to which they are attached may form a ring selected from: C5-C7-cycloalkyl and 5- to 7-membered heterocycloalkyl; optionally wherein the ring is substituted with from 1 to 6 R9groups. R3and R4together with the carbon atoms to which they are attached may form a ring selected from: C5-C7-cycloalkyl and 5- to 7-membered heterocycloalkyl; optionally wherein the ring is substituted with from 1 to 4 R9groups.

[0063] R3and R4together with the carbon atoms to which they are attached may form a C5- C7-cycloalkyl ring; optionally wherein the ring is substituted with from 1 to 6 R9groups. R3and R4together with the carbon atoms to which they are attached may form a C5-C7-cycloalkyl ring; optionally wherein the ring is substituted with from 1 to 4 R9groups.

[0064] R3and R4together with the carbon atoms to which they are attached may form a C5- cycloalkyl ring; optionally wherein the ring is substituted with from 1 to 6 R9groups. R3and R4together with the carbon atoms to which they are attached may form a C5-cycloalkyl ring; optionally wherein the ring is substituted with from 1 to 4 R9groups.

[0065] It may be that R5is independently selected from H, halo, cyano, C1-C4-alkylene- NR7R8, C1-C4-alkylene-OR7, SR7, SOR7, S(O)2R7, S(O)2NR7R7, CO2R7, C(O)R7, C(O)NR7R7, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, O-C0-C4-alkylene-R5c, and C0-C4- alkylene-R5c.

[0066] R5may be H. R5may be C1-C4-alkyl, e.g. methyl.

[0067] R5may be R5c. R5cmay be phenyl optionally substituted with from 1 to 5 R10groups. R5cmay be 5-, or 6-membered heteroaryl optionally substituted with from 1 to 5 R10groups. R5cmay be 6-membered heteroaryl optionally substituted with from 1 to 5 R10groups.

[0068] R4and R5together with the carbon atoms to which they are attached may form a ring selected from: C5-C7-cycloalkyl and 5- to 7-membered heterocycloalkyl; optionally wherein the ring is substituted with from 1 to 6 R9groups. R4and R5together with the carbon atoms to which they are attached may form a ring selected from: C5-C7-cycloalkyl and 5- to 7-membered heterocycloalkyl; optionally wherein the ring is substituted with from 1 to 4 R9groups.

[0069] R4and R5together with the carbon atoms to which they are attached may form a C5- C7-cycloalkyl ring; optionally wherein the ring is substituted with from 1 to 6 R9groups. R4and R5together with the carbon atoms to which they are attached may form a C5-C7-cycloalkyl ring; optionally wherein the ring is substituted with from 1 to 4 R9groups.

[0070] R4and R5together with the carbon atoms to which they are attached may form a C5- cycloalkyl ring; optionally wherein the ring is substituted with from 1 to 6 R9groups. R4and R5together with the carbon atoms to which they are attached may form a C5-cycloalkyl ring; optionally wherein the ring is substituted with from 1 to 4 R9groups.

[0071] Ring B may be independently selected from C5-C7-cycloalkyl, and 5- to 7-membered heterocycloalkyl; optionally wherein Ring B is substituted with from 1 to 6 R9groups. Ring B may be independently selected from C5-C7-cycloalkyl, and 5- to 7-membered heterocycloalkyl; optionally wherein Ring B is substituted with from 1 to 4 R9groups.

[0072] Ring B may be C5-C7-cycloalkyl; optionally substituted with from 1 to 6 R9groups. Ring B may be C5-cycloalkyl; optionally substituted with from 1 to 6 R9groups. Ring B may be C5-C7-cycloalkyl; optionally substituted with from 1 to 6 R9groups. Ring B may be C5- cycloalkyl; optionally substituted with from 1 to 4 R9groups.

[0073] Ring C may be independently selected from C5-C7-cycloalkyl, and 5- to 7-membered heterocycloalkyl; optionally wherein Ring C is substituted with from 1 to 6 R9groups. Ring C may be independently selected from C5-C7-cycloalkyl, and 5- to 7-membered heterocycloalkyl; optionally wherein Ring C is substituted with from 1 to 4 R9groups.

[0074] Ring C may be C5-C7-cycloalkyl; optionally substituted with from 1 to 6 R9groups. Ring C may be C5-cycloalkyl; optionally substituted with from 1 to 6 R9groups. Ring C may be C5-C7-cycloalkyl; optionally substituted with from 1 to 4 R9groups. Ring C may be C5- cycloalkyl; optionally substituted with from 1 to 4 R9groups.

[0075] R9may independently at each occurrence be selected from =O, =S, halo, nitro, cyano, NR7R8, OR7, SR7, SOR7, S(O)2R7, SO2NR7R7, CO2R7, C(O)R7, CONR7R7, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, and C1-C3-alkylene-NR7R8.

[0076] R9may independently at each occurrence be selected from halo, NR7R8, OR7, CO2R7, CONR7R7, C1-C4-alkyl, C1-C3-alkylene-OR7, and C1-C3-alkylene-NR7R8.

[0077] R9may independently at each occurrence be selected from F, Cl, Br, NR7R8, OR7, CO2R7, CONR7R7, C1-C4-alkyl, C1-C3-alkylene-OR7, and C1-C3-alkylene-NR7R8.

[0078] R9may independently at each occurrence be selected from F, NR7R8, OR7, CO2R7, CONR7R7, C1-C4-alkyl, C1-C3-alkylene-OR7, and C1-C3-alkylene-NR7R8.

[0079] R9may independently at each occurrence be selected from F, NR7R8, OR7, CO2R7, CONR7R7, and C1-C4-alkyl.

[0080] R9may independently at each occurrence be selected from OH and C1-C4-alkyl.

[0081] R9amay independently at each occurrence be selected from C3-C8cycloalkyl, phenyl, 3- to 8-membered heterocycloalkyl, and 5-, or 6-membered heteroaryl; wherein where R9aiscycloalkyl, or heterocycloalkyl, R9ais optionally substituted with from 1 to 4 R9groups; and where R9ais phenyl, or heteroaryl, R9ais optionally substituted with from 1 to 5 R10groups.

[0082] R9amay independently at each occurrence be phenyl, optionally substituted with from 1 to 5 R10groups.

[0083] R10may independently at each occurrence be selected from halo, cyano, OR7, C1- C4-alkyl, C1-C4-haloalkyl, C1-C3-alkylene-NR7R8, and C1-C3-alkylene-OR7.

[0084] R10may independently at each occurrence be selected from halo, cyano, OR7, C1- C4-alkyl, and C1-C4-haloalkyl.

[0085] R10may independently at each occurrence be selected from F, Cl, Br, cyano, OR7, C1-C4-alkyl, and C1-C4-haloalkyl.

[0086] R10may independently at each occurrence be selected from F, cyano, OR7, C1-C4- alkyl, and C1-C4-haloalkyl.

[0087] In an embodiment, any of the alkyl, alkylene, alkenyl or cycloalkyl groups are optionally substituted, where chemically possible, by 1 to 5 substituents which are each independently at each occurrence selected from the group consisting of: oxo, fluoro, NRaRb, ORa, and S(O)2Ra; wherein Rais independently at each occurrence selected from H, and C1- C4-alkyl; and Rbis independently at each occurrence selected from H, C1-C4-alkyl, C(O)-C1- C4-alkyl and S(O)2-C1-C4-alkyl.

[0088] It may be that R1is a 3- to 10-membered heterocycloalkyl group having a nitrogen in the ring system, e.g. pyrrolidine, optionally substituted with C0-C6-alkylene-R9aand / or from 1 to 6 R9groups; and R4and R5together with the carbon atoms to which they are attached form a C5-C7-cycloalkyl ring; optionally wherein the ring is substituted with from 1 to 6 R9groups.

[0089] It may be that R1is a 3- to 10-membered heterocycloalkyl group having a nitrogen in the ring system, e.g. pyrrolidine, optionally substituted with C0-C6-alkylene-R9aand / or from 1 to 6 R9groups; and R4and R5together with the carbon atoms to which they are attached form a C5-cycloalkyl ring; optionally wherein the ring is substituted with from 1 to 6 R9groups.

[0090] It may be that R1is a 3- to 10-membered heterocycloalkyl group having a nitrogen in the ring system, e.g. pyrrolidine, optionally substituted with C0-C6-alkylene-R9aand / or from 1 to 6 R9groups; and Ring C is a C5-C7-cycloalkyl ring; optionally substituted with from 1 to 6 R9 groups.

[0091] It may be that R1is a 3- to 10-membered heterocycloalkyl group having a nitrogen in the ring system, e.g. pyrrolidine, optionally substituted with C0-C6-alkylene-R9aand / or from 1 to 6 R9groups; and Ring C is C5-cycloalkyl; optionally substituted with from 1 to 6 R9groups..

[0092] In an embodiment, the compound of formula (I) is selected from: , , , , .g. ,, , ,.g. .g. ), nd(e.g. ).

[0093] In accordance with a second aspect, the present invention provides a pharmaceutical composition comprising a compound defined in the first aspect, and one or more pharmaceutically acceptable excipients.

[0094] In accordance with a third aspect, the present invention provides a compound as defined in the first aspect or a pharmaceutical composition as defined in the second aspect, for use as a medicament.

[0095] In accordance with a fourth aspect, the present invention provides the use of a compound as defined in the first aspect or a pharmaceutical composition as defined in the second aspect, for the manufacture of a medicament.

[0096] In accordance with a fifth aspect, the present invention provides a compound as defined in the first aspect, or a pharmaceutical composition as defined in the second aspect, for use in a method of treatment or prophylaxis of a disease of the musculoskeletal system, a disease of the skin, a metabolic disease, a disease of the Nervous System, a Cardiovascular disease, an Endocrine disorder, a disease of the eye, a disease affecting the urogenital system, a haemic or lymphatic condition, a respiratory disease, an inflammatory or autoimmune condition, a disease of the Gastrointestinal system, a Neoplasm, cancer, or a disease or disorder selected from Amelogenesis Imperfecta, Anodontia, Odontodysplasia, Branchio-Oto-Renal Syndrome, Sotos Syndrome, and Waardenburg's Syndrome.

[0097] In accordance with a sixth aspect, the present invention provides a method for the treatment or prophylaxis of a disease of the musculoskeletal system, a disease of the skin, a metabolic disease, a disease of the Nervous System, a Cardiovascular disease, an Endocrine disorder, a disease of the eye, a disease affecting the urogenital system, a haemic or lymphatic condition, a respiratory disease, an inflammatory or autoimmune condition, a disease of the Gastrointestinal system, a Neoplasm, cancer, or a disease or disorder selected from Amelogenesis Imperfecta, Anodontia, Odontodysplasia, Branchio-Oto-Renal Syndrome, Sotos Syndrome, and Waardenburg's Syndrome, said method comprising administering to a subject, an effective amount of a compound as defined in the first aspect, or a pharmaceutical composition as defined in the second aspect.

[0098] In accordance with a seventh aspect, the present invention provides a compound as defined in the first aspect, or a pharmaceutical composition as defined in the second aspect, for use in a method of treatment or prophylaxis of a disease selected from: Recessive dystrophic epidermolysis bullosa, Junctional epidermolysis bullosa, Xeroderma pigmentosum, Netherton syndrome, Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, Cystic Fibrosis, Alport syndrome, Dravet Syndrome, Aniridia, Methylmalonic Acidemia, Colorectal Cancer, Endometrium Cancer, Breast Cancer, Ovarian Cancer, Lung Squamous Cell Carcinoma, Head and Neck Squamous Cell Carcinoma, Familial adenomatous polyposis, Hemophilia A, Hemophilia B, Choroideremia, Pulmonary Artery Hypertension, Ataxia telangiectasia, Shwachman-Diamond syndrome, Mucopolysaccharidosis Type I, Mucopolysaccharidosis Type VI, Mucopolysaccharidosis type III, Niemann-Pick Disease, Primary Ciliary Dyskinesia, Usher syndrome, and Retinitis Pigmentosa.

[0099] In accordance with an eighth aspect, the present invention provides a method for the treatment or prophylaxis of a disease selected from: Recessive dystrophic epidermolysis bullosa, Junctional epidermolysis bullosa, Xeroderma pigmentosum, Netherton syndrome, Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, Cystic Fibrosis, Alport syndrome, Dravet Syndrome, Aniridia, Methylmalonic Acidemia, Colorectal Cancer, Endometrium Cancer, Breast Cancer, Ovarian Cancer, Lung Squamous Cell Carcinoma, Head and Neck Squamous Cell Carcinoma, Familial adenomatous polyposis, Hemophilia A, Hemophilia B, Choroideremia, Pulmonary Artery Hypertension, Ataxia telangiectasia, Shwachman-Diamond syndrome, Mucopolysaccharidosis Type I, Mucopolysaccharidosis Type VI, Mucopolysaccharidosis type III, Niemann-Pick Disease, Primary Ciliary Dyskinesia, Usher syndrome, and Retinitis Pigmentosa.

[0100] In accordance with a ninth aspect, the present invention provides the use of a compound as defined in the first aspect, or a pharmaceutical composition as defined in the second aspect for the manufacture of a medicament for the treatment or prophylaxis of a disease of the musculoskeletal system, a disease of the skin, a metabolic disease, a disease of the Nervous System, a Cardiovascular disease, an Endocrine disorder, a disease of the eye, a disease affecting the urogenital system, a haemic or lymphatic condition, a respiratory disease, an inflammatory or autoimmune condition, a disease of the Gastrointestinal system, a Neoplasm, cancer, or a disease or disorder selected from Amelogenesis Imperfecta, Anodontia, Odontodysplasia, Branchio-Oto-Renal Syndrome, Sotos Syndrome, and Waardenburg's Syndrome.

[0101] In accordance with a tenth aspect, the present invention provides a method of allowing translational read-through of PTC mutations in a subject, said method comprising administering to a subject an effective amount of a compound as defined in the first aspect, or a pharmaceutical composition as defined in the second aspect.

[0102] In accordance with an eleventh aspect, the present invention provides a compound as defined in the first aspect, or a pharmaceutical composition as defined in the second aspect, for use in a method of treating conditions or disorders which are associated with a PTC mutation in a subject, said method comprising administering to a subject an effective amount of a compound as defined in the first aspect, or a pharmaceutical composition as defined in the second aspect.

[0103] In accordance with a twelfth aspect, the present invention provides a method of treating conditions or disorders which are associated with a PTC mutation in a subject, said method comprising administering to a subject an effective amount of a compound as defined in the first aspect, or a pharmaceutical composition as defined in the second aspect.

[0104] Suitably a PTC mutation may be any mutation which generates a premature termination codon (PTC) in a gene. Suitably a PTC mutation may be any mutation which generates an in-frame premature termination codon (PTC) in a gene. Suitably a PTC mutation occurs in the nucleotide sequence of a gene. Suitably a PTC mutation may occur in the coding region or non-coding region of a gene. Suitably a PTC mutation may occur in the coding region of a gene.

[0105] Suitably the mutation may be a point mutation, for example a substitution, deletion or insertion mutation. Suitably the mutation may be a substitution mutation. Suitably the substitution mutation may replace one nucleotide with another different nucleotide, suitably within the nucleotide sequence of a gene. Suitably the mutation may therefore be regarded as a nonsense mutation. Suitably the mutation may be a nonsense mutation which causes an in-frame PTC in a gene. Suitably the PTC may be any known termination codon such as TAG, TAA or TGA. Suitably the PTC may be TGA. Suitably therefore in some embodiments, the PTC mutation may be a substitution mutation which generates a PTC comprising TAG, TAA or TGA in a gene. Suitably therefore in some embodiments, the PTC mutation may be a substitution mutation of CGA to TGA or CAG to TAG in a gene.

[0106] A condition or disorder associated with a PTC mutation in a subject may be a condition or disorder which is directly or indirectly caused by a PTC mutation in a subject. Suitably a condition or disorder associated with a PTC mutation in a subject may be a condition or disorder which is directly caused by a PTC mutation in a subject. Suitably a condition or disorder associated with a PTC mutation in a subject may be a condition or disorder which is caused by a PTC mutation in one or more genes in a subject. Suitably a condition or disorder associated with a PTC mutation in a subject may be a condition or disorder which is directly caused by a PTC mutation in one or more genes in a subject. Suitably a condition or disorder associated with a PTC mutation in a subject may be a condition or disorder which is caused by a PTC mutation in one or more genes in a subject leading to a loss of function of the or each gene. Suitably reference herein to ‘a’ PTC mutation may be understood to refer to one or more PTC mutations, or a plurality of PTC mutations, suitably which may be present in one or more genes in a subject.

[0107] Suitably the one or more genes in which the PTC mutation is present are genes relating to one or more diseases as described herein. Suitably the one or more genes may be directly or indirectly linked with one or more diseases described herein. Suitably the one or more genes may contribute to, or cause, the phenotype of one or more diseases described herein. Such genes may be for example LAMB3, COL7A, COL4, CFTR, and DMD, which are each associated with one or more of the diseases identified herein. In some embodiments, forexample in which the disease is cancer, the one or more genes in which the PTC mutation is present may be cell cycle genes, tumour suppressor genes etc. Such tumour suppressor genes may include, for example, TP53, PTEN, APC, ARID1A or CTCF. Suitably such mutations may be regarded as driver mutations, suitably which drive a disease phenotype, such as tumour growth. Therefore, in some embodiments, the PTC mutation may be regarded as a driver mutation. In other embodiments, the one or more genes in which the PTC mutation is present may not contribute to or cause the disease phenotype. Suitably such mutations may be regarded as bystander mutations. Therefore in some embodiments, the PTC mutation may be regarded as a bystander mutation.

[0108] Conditions or disorders associated with a PTC mutation are well known in the art, and suitable such disorders which may be treated or prevented by the present invention are described hereinbelow. However, suitably, such disorders that are associated with PTC mutations may also be identified or determined by the use of standard molecular biology techniques. Suitably a condition or disorder may be determined as being associated with a PTC mutation by the use of molecular biology techniques, such as sequencing, single strand conformational polymorphism, denaturing gradient gel electrophoresis, heteroduplex analysis, or restriction fragment length polymorphism. Suitably a PTC mutation present in one or more genes of a subject which may cause a disease or condition can be identified using such techniques. Suitably, whole genome sequencing or whole exome sequencing may be used to identify a PTC mutation in one or more genes of a subject, suitably which may cause a disease or condition. Suitable methodologies may be described in Karagiannakos et al. Cancers (Basel) 2022, 14, 664, Stark et al. ‘A prospective evaluation of whole-exome sequencing as a first-tier molecular test in infants with suspected monogenic disorders’ Genetics in Medicine, Volume 18, Issue 11, 2016, North et al. ‘Approach to the diagnosis of congenital myopathies’ Neuromuscular Disorders, Volume 24, Issue 2, 2014, for example.

[0109] Suitably such techniques may be applied to a sample obtained from a subject suffering from a disease or condition or suspected of suffering from a disease or condition, suitably which may be caused by a PTC mutation. Suitably such techniques may comprise comparing a result from said sample, to a result obtained from a reference sample. Suitably a reference sample may be a sample of the same type from a healthy subject, suitably from an equivalent healthy subject of the same age, nationality, race, height, weight etc. Suitable samples may include: a blood sample, serum sample, CNS fluid sample, tissue sample, cell sample, and the like. Suitably comparing a result in the context of the techniques above may comprise comparing the sequence of one or more genes from the subject suffering from a disease or condition to the sequence of the same one or more genes of the healthy subject.Suitably to identify PTC mutations within the one or more genes of the subject suffering from a disease or condition. Suitably such sequence comparisons may be carried out by available software, such as alignment software.

[0110] PTC read-through agents, such as the compounds disclosed herein, may in one or more embodiments, be of value and used in the treatment or amelioration of the following non- limiting examples of disorders and diseases. Suitably any of the following disorders and diseases may be regarded as a disease or disorder associated with a PTC mutation in a subject. Suitably therefore the present invention provides a method of treating conditions or disorders which are associated with PTC mutations in a subject, wherein the conditions or disorders are selected from any listed in the following paragraphs.

[0111] The disease may be a disease of the musculoskeletal system. The disease of the musculoskeletal system may be a disease selected from Shwachman-Diamond Syndrome, Rickets, Laron Syndrome, Muscular Dystrophies (e.g. Duchenne muscular dystrophy (DMD)), Microcephaly, congenital limb deformities, Muscle Spasticity, Dwarfism, Gigantism, Osteopoikilosis, Cleidocranial Dysplasia, Synostosis, Mitochondrial Myopathies and Encephalomyopathies, Craniosynostoses, Mandibulofacial Dysostosis, Scoliosis, Osteoporosis, Osteopetrosis, Hyperostosis, Osteosclerosis, Osteogenesis Imperfecta, Holoprosencephaly, Acromegaly, Arthrogryposis, and Campomelic Dysplasia.

[0112] The disease may be a disease of the skin. The disease of the skin may be a disease selected from Ectodermal Dysplasia, Epidermolysis Bullosa, Focal Dermal Hypoplasia, Ichthyosis Vulgaris, Autosomal Recessive Congenital Ichthyosis (ARCI), Recessive X-linked Ichthyosis, Lamellar Ichthyosis, Congenital Ichthyosiform Erythroderma, Harlequin Ichthyosis, Epidermolytic Ichthyosis, Superficial Epidermolytic Ichthyosis, CHILD syndrome, Netherton syndrome, MEDNIK syndrome, Neutral lipid storage disease with ichthyosis, Atopic Dermatitis, Alopecia, Atrichia with papular lesions, Hypotrichosis, Incontinentia Pigmenti, Epidermolysis Bullosa Simplex, Lipodystrophy, Hidradenitis Suppurativa, Hyperpigmentation, Junctional Epidermolysis Bullosa, Oculocutaneous Albinism, Chronic Mucocutaneous Candidiasis, Chronic Mucocutaneous Ichthyosis, X-Linked Hypopigmentation, Cutis Laxa, Menkes Kinky Hair Syndrome, Palmoplantar Keratoderma, Ehlers-Danlos Syndrome, Congenital Monilethrix, Onychomycosis, Benign Familial Pemphigus, Albinism; Kindler syndrome, Cowden Syndrome, Xeroderma pigmentosum, epidermodysplasia verruciformis, Lipoid proteinosis, dyschromatosis symmetrica hereditaria, Striate keratodermas, Autosomal Recessive Congenital Anonychia, Focal dermal hypoplasia, and Skin fragility / woolly hair syndrome.

[0113] The disease may be a metabolic disease. The metabolic disease may be selected from Congenital Adrenal Hyperplasia, Inborn errors of Amino Acid Metabolism, Hypertriglyceridemia, Diabetes Mellitus, Type 1 and Type 2, Glycogen Storage Disease, Optic Atrophy, Calcinosis, Multiple Sulfatase Deficiency Disease, Fabry Disease, Hyperinsulinism, Familial Hypophosphatemia, Pseudohypoaldosteronism, Tangier Disease, Amyotrophic Lateral Sclerosis, Lactic Acidosis, Familial Amyloidosis, Mucopolysaccharidosis, Anemia, Sandhoff Disease, Cytochrome-c Oxidase Deficiency, Pyruvate Dehydrogenase Complex Deficiency Disease, Hypoglycemia, Neuronal Ceroid-Lipofuscinoses, Severe Combined Immunodeficiency, , Chronic Idiopathic Jaundice, Progeria, Hyponatremia, Wasting Syndrome, Cystinuria, Glycogen Storage Disease, Gaucher Disease, Hypolipoproteinemias, Oculocerebrorenal Syndrome, Smith-Lemli-Opitz Syndrome, Adrenoleukodystrophy, Ataxia Telangiectasia, Canavan Disease, Carbamoyl-Phosphate Synthase I Deficiency Disease, beta-Mannosidosis, and lysosomal storage diseases, wherein the lysosomal storage disease may be selected from Niemann-Pick Disease Mucopolysaccharidosis type 1 (Hurler syndrome), Mucopolysaccharidosis type 6, Mucopolysaccharidosis type 7, CLN1 disease, and CL3 disease.

[0114] The disease may be a disease of the Nervous System. The disease of the Nervous System may be selected from Rett Syndrome, Ataxias, Sensorineural Hearing Loss, Epilepsy, Charcot-Marie-Tooth Disease, Spinal Muscular Atrophy, Spastic Paraplegia, Hydrocephalus, Migraine with Aura, Chorea, Tremor, Usher Syndromes, De Lange Syndrome, Duane Retraction Syndrome, Dementia, Myoclonus, Hereditary Sensory and Autonomic Neuropathies, Intellectual Disability, X-linked Mental Retardation, Fragile X Syndrome, Hypopituitarism, Leukoencephalopathies, Dystonia, Congenital Pain Insensitivity, Tourette Syndrome, Alzheimers Disease, Parkinsons Disease, Angelman Syndrome, Apraxias, Cerebral Palsy, and Frontotemporal Dementia.

[0115] The disease may be a Cardiovascular disease. The cardiovascular disease may be selected from Coronary Disease, Ventricular Fibrillation, Telangiectasis, Kartagener Syndrome, Alagille Syndrome, Andersen Syndrome, Atrioventricular Block, and Cardiomyopathies.

[0116] The disorder may be an Endocrine disorder. The Endocrine disorder may be selected from Hypogonadism, Goiter, Fetal Macrosomia, Thyroid Hormone Resistance Syndrome, Gonadal Dysgenesis, Hypoparathyroidism, Neurogenic Diabetes Insipidus, and Androgen- Insensitivity Syndrome.

[0117] The disease may be a disease of the eye. The disease of the eye may be selected from Leber syndrome, Hereditary Optic Atrophies, Ectopia Lentis, Coloboma, Aphakia, and Choroideremia.

[0118] The disease may be a disease affecting the urogenital system. The disease affecting the urogenital system may be selected from Hypospadias, Hydrops Fetalis, Interstitial Nephritis, Polycystic Kidney Diseases, Azoospermia, Alport Syndrome and Azoospermia.

[0119] The disease or disorder may be a haemic or lymphatic condition. The haemic or lymphatic condition may be selected from alpha- and beta-Thalassemia, Afibrinogenemia, Hemophagocytic Lymphohistiocytosis, Factor XI Deficiency, Hemophilia A, von Willebrand Diseases, Factor V Deficiency, Sideroblastic Anemia, Hereditary Elliptocytosis, Neutropenia, Chronic Granulomatous Disease, Hereditary Spherocytosis, Polycythemia, Hemophilia B, Factor VII Deficiency, Bernard-Soulier Syndrome, Dyserythropoietic Anemia,Hemolytic Anemia, Idiopathic Thrombocytopenic Purpura, Thrombasthenia, Factor XIII Deficiency, Hepatoerythropoietic Porphyria, and Acute Intermittent Porphyria.

[0120] The disease may be a respiratory disease. The respiratory disease may be selected from Cystic Fibrosis, Pulmonary Hypertension, Lipoid Proteinosis of Urbach and Wiethe, Newborn Respiratory Distress Syndrome, Chronic Obstructive Pulmonary Disease, Chronic Obstructive, Asthma, and Choanal Atresia.

[0121] The disease or disorder may be an inflammatory or autoimmune condition. The inflammatory or autoimmune condition may be selected from Immunologic Deficiency Syndromes, and Leukocyte-Adhesion Deficiency Syndrome.

[0122] The disease may be a disease of the Gastrointestinal system. Diseases of the gastrointestinal system may be selected from Chronic Hepatitis B, Colitis, Intestinal Polyposis, Inflammatory Bowel Diseases, Hirschsprung Disease, Exocrine Pancreatic Insufficiency, Crohn’s Disease, and Cholestasis.

[0123] The disease or disorder may be a Neoplasm. The Neoplasm may be selected from Acute Myeloid Leukemia, Paraganglioma, Rhabdoid Tumor, Rhabdomyoma, Adenoid Cystic Carcinoma, Large Cell Carcinoma, Lobular Carcinoma, Skin Appendage Carcinoma, Squamous Cell Carcinoma, Alveolar Rhabdomyosarcoma, Neuroectodermal Tumors, Multiple Hamartoma Syndrome, Pheochromocytoma, Nevus, Osteosarcoma, Teratoma, and Adenoma.

[0124] The disease or disorder may be cancer. The cancer may be selected from acoustic neuroma, anal cancer, bladder cancer, Bowen's disease, brain cancer, breast cancer, carcinomas including basal cell carcinoma, bile duct carcinoma, bronchogenic carcinoma,choriocarcinoma, embryonal carcinoma, cystadenocarcinoma, epithelial carcinoma, medullary carcinoma, NUT midline carcinoma (NMC), papillary carcinoma, papillary adenocarcinomas, renal cell carcinoma, sebaceous gland carcinoma, small cell lung carcinoma, squamous cell carcinoma, and sweat gland carcinoma, cervical cancer, chordoma, colon cancer, colorectal cancer, craniopharyngioma, dysproliferative changes (dysplasias and metaplasias), endometrial cancer, ependymoma, esophageal cancer, essential thrombocythemia, estrogen-receptor positive breast cancer, Ewing’s tumour, genital cancer, cancer of the cervix, cancer of the vulva, vulvar intraepithelial neoplasia (VIN), cancer of the vagina, germ cell testicular cancer, gastrointestinal cancers, gastric cancer, glioblastoma, glioma, heavy chain disease, hemangioblastoma, hepatocellular cancer, hepatoma, hormone insensitive prostate cancer, keratinocyte carcinomas, kidney cancer, leukaemias including acute leukaemia, acute lymphocytic leukaemia, acute myeloid leukaemia, acute myelocytic leukaemia (monocyctic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute t-cell leukaemia, chronic leukaemia, chronic lymphocytic leukaemia, chronic myelocytic (granulocytic) leukaemia, chronic myelogenous leukaemia, erythroleukemia, lymphoblastic leukaemia, and myelogenous leukaemia, liver cancer, lung cancer, lymphoid malignancies of T-cell or B-cell origin, lymphomas (Hodgkin’s and non-Hodgkin’s) including cutaneous T-cell lymphoma, diffuse large B-cell lymphoma, and follicular lymphoma, cutaneous (skin) lymphomas, malignancies and hyperproliferative disorders including of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, advanced malignancies, medulloblastoma, melanoma, meningioma, Merkel cell cancer mesothelioma, metastatic cancer, multiple myeloma, myeloma, pancreatic cancer, myelofibrosis, myeloproliferative neoplasms, neuroblastoma, non-small cell lung cancer, head and neck cancer, oligodendroglioma, oral cancer, ovarian cancer, pancreatic cancer, pinealoma, polycythemia vera, prostate cancer, rectal cancer, retinoblastoma, sarcomas including chondrosarcoma, endotheliosarcoma, fibrosarcoma, gliosarcoma, leiomyosarcoma, liposarcoma, lymphagioendotheliosarcoma, lymphangiosarcoma, myxosarcoma, Castleman's disease and Kaposi's sarcoma, osteogenic sarcoma, and rhabdomyosarcoma, seminoma, skin cancer, skin adnexal tumors, and sarcomas, small cell lung cancer, solid tumors, stomach cancer, synovioma, testicular tumours, thyroid cancer, uterine cancer, Waldenstrom’s macroglobulinemia, and Wilms’ tumour.

[0125] The disease or disorder may be selected from Amelogenesis Imperfecta, Anodontia, Odontodysplasia, Branchio-Oto-Renal Syndrome, Sotos Syndrome, and Waardenburg's Syndrome.

[0126] The disease or disorder may be selected from: Recessive dystrophic epidermolysis bullosa, Junctional epidermolysis bullosa, Xeroderma pigmentosum, Netherton syndrome, Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, Cystic Fibrosis, Dravet Syndrome, Aniridia, Methylmalonic Acidemia, Colorectal Cancer, Endometrium Cancer, Breast Cancer, Ovarian Cancer, Lung Squamous Cell Carcinoma, Head and Neck Squamous Cell Carcinoma, Familial adenomatous polyposis, Hemophilia A, Hemophilia B, Choroideremia, Pulmonary Artery Hypertension, Ataxia telangiectasia, Shwachman-Diamond syndrome, Mucopolysaccharidosis Type I, Mucopolysaccharidosis Type VI, Mucopolysaccharidosis type III, Niemann-Pick Disease, Primary Ciliary Dyskinesia, and ciliopathies (such as Usher syndrome or Retinitis Pigmentosa).

[0127] The disease or disorder may be selected from: Recessive dystrophic epidermolysis bullosa, Junctional epidermolysis bullosa, Duchenne Muscular Dystrophy, Cystic Fibrosis, Colorectal Cancer, Endometrium Cancer, Breast Cancer, Ovarian Cancer, Lung Squamous Cell Carcinoma, Head and Neck Squamous Cell Carcinoma and Familial adenomatous polyposis. Suitably such disorders may be associated with a PTC mutation in a subject. Suitably for example, the disease may be Junctional epidermolysis bullosa, associated with a PTC mutation in the LAMB3 gene. Suitably for example, the disease may be Recessive dystrophic epidermolysis bullosa, associated with a PTC mutation in the COL7A1 gene. Suitably for example, the disease may be Duchenne Muscular Dystrophy, associated with a PTC mutation in the DMD gene. Suitably for example, the disease may be Cystic Fibrosis associated with a PTC mutation in the CTFR gene. Suitably for example, the disease may be Familial adenomatous polyposis associated with a PTC mutation in the APC gene. Suitably for example, the disease may be a cancer as listed above associated with a PTC mutation in a gene selected from: TP53, PTEN, ARID1A or CTCF.

[0128] Suitably therefore the present invention provides a method of treating conditions or disorders which are associated with PTC mutations in a subject, wherein the condition or disorder associated with PTC mutations in a subject is selected from recessive dystrophic epidermolysis bullosa, Junctional epidermolysis bullosa, Xeroderma pigmentosum, Netherton syndrome, Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, Cystic Fibrosis, Dravet Syndrome, Aniridia, Methylmalonic Acidemia, Familial adenomatous polyposis, Hemophilia A, Hemophilia B, Choroideremia, Pulmonary Artery Hypertension, Ataxia telangiectasia, Shwachman-Diamond syndrome, Mucopolysaccharidosis Type I, Mucopolysaccharidosis Type VI, Mucopolysaccharidosis type III, Niemann-Pick Disease, Primary Ciliary Dyskinesia, Ciliopathies (such as Usher syndrome or Retinitis Pigmentosa) and Alport Syndrome. In some embodiments, the present invention provides a method oftreating conditions or disorders which are associated with PTC mutations in a subject, wherein the condition or disorder associated with PTC mutations in a subject is selected from recessive dystrophic epidermolysis bullosa, Junctional epidermolysis bullosa, Duchenne Muscular Dystrophy, Cystic Fibrosis, and Familial adenomatous polyposis.

[0129] PTC read-through agents, such as the compounds disclosed herein, may in one or more embodiments, also be of value and used in the palliation, diagnosis or prevention of any disease, disorder or condition in humans of one or more of the aforesaid non-limiting examples of disorders and diseases. Suitably any of the aforesaid disorders and diseases may be regarded as a disease or disorder associated with a PTC mutation in a subject. Suitably therefore the present invention further provides a method of palliation, diagnosis or prevention of conditions or disorders which are associated with PTC mutations in a subject, wherein the conditions or disorders are selected from any listed in the aforesaid paragraphs.

[0130] Treatment or amelioration with PTC read-through agents, such as compositions comprising the compounds disclosed herein or salts thereof (or combinations thereof), in some embodiments may be effective if administered orally. In some other embodiments may be effective if applied topically, and in some further embodiments may be effective if applied topically and orally.

[0131] In some embodiments, compositions comprising a novel compound disclosed herein or salt thereof (or combinations thereof) may be administered to young children. In some embodiments, compositions comprising a compound of the invention or salt thereof (or combinations thereof) may be administered to adolescents or teenagers. In some embodiments, compositions comprising a compound of the invention or salt thereof (or combinations thereof) may be administered to adults.

[0132] The disclosure may also be defined according to any one of the following numbered clauses: 1. A compound of formula (I), or a tautomeric form thereof, or a pharmaceutically acceptable salt or N-oxide thereof:(I)wherein X is N or CR6; R1is independently selected from C0-C6-alkylene-R1a, and C2-C6-alkylene-R1b; R1ais independently selected from C3-C8cycloalkyl, C5-C8cycloalkenyl, 3- to 10-membered heterocycloalkyl, and 5- to 10-membered heterocycloalkenyl; wherein R1ais optionally substituted with from 1 to 4 R9groups; wherein where R1ais heterocycloalkyl or heterocycloalkenyl, the heterocycloalkyl or heterocycloalkenyl is optionally fused to a phenyl ring, wherein the phenyl ring is optionally substituted with from 1 to 4 R10groups; R1bis independently selected from NR7aR8aand OR7; wherein R1comprises at least one nitrogen atom; R2ais independently at each occurrence selected from H and C1-C4alkyl; R2bis independently at each occurrence selected from H, C1-C4alkyl, C0-C4alkyl-R2c, C(O)- C1-C4-alkyl, S(O)-C1-C4-alkyl, and S(O)2-C1-C4-alkyl; R2cis independently selected from C3-C8cycloalkyl, C5-C8cycloalkenyl, phenyl, 3- to 8- membered heterocycloalkyl, 5- to 8-membered heterocycloalkenyl and 5-, or 6-membered heteroaryl; wherein where R2cis cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, R2cis optionally substituted with from 1 to 4 R9groups; and where R2cis phenyl, or heteroaryl, R5cis optionally substituted with from 1 to 5 R10groups; or R2aand R2b, together with the nitrogen atom to which they are attached, form a 5- to 8-membered heterocycloalkyl ring; optionally substituted with 1 to 4 R9groups; R3is independently selected from H, cyano, C1-C4-alkylene-NR7R8, NR7R8, C1-C4-alkylene- OR7, OR7, SR7, SOR7, S(O)2R7, S(O)2NR7R7, CO2R7, C(O)R7, C(O)NR7R7, C1-C4-alkyl, C2-C4- alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, NR7-C0-C4-alkylene-R3c, O-C0-C4-alkylene-R3c, and C0-C4-alkylene-R3c; R3cis independently selected from C3-C8cycloalkyl, C5-C8 cycloalkenyl, phenyl, 3- to 10- membered heterocycloalkyl, 5- to 10-membered heterocycloalkenyl and 5-, or 6-membered heteroaryl; wherein where R3cis cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, R3cis optionally substituted with from 1 to 4 R9groups; and where R3cis phenyl or heteroaryl, R3cis optionally substituted with from 1 to 5 R10groups; R4is independently selected from H, halo, cyano, NR7bR8, OR7, SR7, SOR7, S(O)2R7, S(O)2NR7R7, CO2R7, C(O)R7, C(O)NR7R7, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4- haloalkyl, O-C0-C4-alkylene-R4c, and C0-C4-alkylene-R4c;R4cis independently selected from C3-C8cycloalkyl, C5-C8cycloalkenyl, 3- to 10-membered heterocycloalkyl, 5- to 10-membered heterocycloalkenyl and 5-membered heteroaryl; wherein where R4cis cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, R4cis optionally substituted with from 1 to 4 R9groups; and where R4cis heteroaryl, R4cis optionally substituted with from 1 to 5 R10groups; R5is independently selected from H, halo, cyano, C1-C4-alkylene-NR7R8, NR7bR8, C1-C4- alkylene-OR7, OR7b, SR7, SOR7, S(O)2R7, S(O)2NR7R7, CO2R7, C(O)R7, C(O)NR7R7, C1-C4- alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, NR7-C0-C4-alkylene-R5c, O-C0-C4- alkylene-R5c, and C0-C4-alkylene-R5c; R5cis independently selected from C3-C8cycloalkyl, C5-C8cycloalkenyl, phenyl, 3- to 10- membered heterocycloalkyl, 5- to 10-membered heterocycloalkenyl and 5-, or 6-membered heteroaryl; wherein where R5cis cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, R5cis optionally substituted with from 1 to 4 R9groups; and where R5cis phenyl or heteroaryl, R5cis optionally substituted with from 1 to 5 R10groups; or R3and R4together with the carbon atoms to which they are attached form a ring selected from: phenyl, C5-C7-cycloalkyl, 5- to 7-membered heterocycloalkyl and 5- or 6- membered heteroaryl; wherein where the ring is cycloalkyl or heterocycloalkyl, it is optionally substituted with from 1 to 4 R9groups and where the ring is phenyl or heteroaryl, it is optionally substituted with from 1 to 4 R10groups; or R4and R5together with the carbon atoms to which they are attached form a ring selected from: phenyl, C5-C7-cycloalkyl, 5- to 7-membered heterocycloalkyl and 5- or 6- membered heteroaryl; wherein where the ring is cycloalkyl or heterocycloalkyl, it is optionally substituted with from 1 to 4 R9groups and where the ring is phenyl or heteroaryl, it is optionally substituted with from 1 to 4 R10groups; R6is independently selected from H, halo, C1-C6-alkyl, and C1-C6-haloalkyl; R7and R7aare each independently at each occurrence selected from H and C1-C4alkyl; R7bis independently at each occurrence selected from C1-C4alkyl; R8is independently at each occurrence selected from H, C1-C4alkyl, C1-C4-haloalkyl and C(O)-C1-C4-alkyl R8ais independently at each occurrence selected from H, C1-C4alkyl, C1-C4-haloalkyl, C(O)- C1-C4-alkyl and phenyl optionally substituted with from 1 to 5 R10groups; or R7aand R8a, together with the nitrogen atom to which they are attached, form a 5- to 8-membered heterocycloalkyl ring; optionally substituted with 1 to 4 R9groups;R9is independently at each occurrence selected from =O, =S, halo, nitro, cyano, NR7R8, OR7, SR7, SOR7, S(O)2R7, SO2NR7R7, CO2R7, C(O)R7, CONR7R7, C1-C4-alkyl, C2-C4-alkenyl, C2- C4-alkynyl, C1-C4-haloalkyl, C3-C6-cycloalkyl, C1-C3-alkylene-NR7R8, and C0-C3-alkylene- phenyl; R10is independently at each occurrence selected from halo, nitro, cyano, NR7R8, OR7, SR7, SOR7, S(O)2R7, SO2NR7R7, CO2R7, C(O)R7, CONR7R7, C1-C4-alkyl, C2-C4-alkenyl, C2-C4- alkynyl, C1-C4-haloalkyl, C3-C6-cycloalkyl, C1-C3-alkylene-NR7R8, and C1-C3-alkylene-OR7; and wherein any of the aforementioned alkyl, alkylene, alkenyl, or cycloalkyl groups is optionally substituted, where chemically possible, by 1 to 5 substituents which are each independently at each occurrence selected from the group consisting of: C1-C4-alkyl, oxo, halo, nitro, cyano, NRaRb, ORa, SRa, CO2Ra, C(O)Ra, CONRaRa, S(O)Ra, and S(O)2Ra; wherein Rais independently at each occurrence selected from H, and C1-C4-alkyl; and Rbis independently at each occurrence selected from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and S(O)2-C1-C4-alkyl. 2. A compound according to clause 1, wherein X is N. 3. A compound according to clause 1 or clause 2, wherein R2aand R2bare each H. 4. A compound according to any one of clauses 1 to 3, wherein R1comprises at least one amine nitrogen. 5. A compound according to any one of clauses 1 to 4, wherein R1is C0-C6-alkylene- R1a. 6. A compound according to clause 5, wherein R1is R1a. 7. A compound according to clause 5 or clause 6, wherein R1ais a 3- to 10-membered heterocycloalkyl group having a nitrogen in the ring system. 8. A compound according to any one of clauses 1 to 7, wherein R3is H. 9. A compound according to any one of clauses 1 to 7, wherein R3is C1-C4-alkyl. 10. A compound according to any one of clauses 1 to 9, wherein R4is H. 11. A compound according to any one of clauses 1 to 9, wherein R4is C1-C4-alkyl. 12. A compound according to any one of clauses 1 to 11, wherein R5is R5c. 13. A compound according to any one of clauses 1 to 12, wherein R5cis phenyl optionally substituted with from 1 to 5 R10groups.14. A compound according to any one of clauses 1 to 12, wherein R5cis 6-membered heteroaryl optionally substituted with from 1 to 5 R10groups. 15. A compound according to any one of clauses 1 to 11, wherein R5is H. 16. A compound according to any one of clauses 1 to 11, wherein R5is C1-C4-alkyl. 17. A pharmaceutical composition comprising a compound according to any one of clauses 1 to 16, and one or more pharmaceutically acceptable excipients. 18. A compound according to any one of clauses 1 to 16, or a pharmaceutical composition according to clause 17, for use as a medicament. 19. A compound according to any one of clauses 1 to 16, or a pharmaceutical composition according to clause 17, for use in the treatment of: a disease of the musculoskeletal system, a disease of the skin, a metabolic disease, a disease of the Nervous System, a Cardiovascular disease, an Endocrine disorder, a disease of the eye, a disease affecting the urogenital system, a haemic or lymphatic condition, a respiratory disease, an inflammatory or autoimmune condition, a disease of the Gastrointestinal system, a Neoplasm, cancer, or a disease or disorder selected from Amelogenesis Imperfecta, Anodontia, Odontodysplasia, Branchio-Oto-Renal Syndrome, Sotos Syndrome, and Waardenburg's Syndrome. 20. A compound according to any one of clauses 1 to 16, or a pharmaceutical composition according to clause 17, for use in the treatment of a disease selected from: Recessive dystrophic epidermolysis bullosa, Junctional epidermolysis bullosa, Xeroderma pigmentosum, Netherton syndrome, Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, Cystic Fibrosis, Dravet Syndrome, Aniridia, Methylmalonic Acidemia, Colorectal Cancer, Endometrium Cancer, Breast Cancer, Ovarian Cancer, Lung Squamous Cell Carcinoma, Head and Neck Squamous Cell Carcinoma, Familial adenomatous polyposis, Hemophilia A, Hemophilia B, Choroideremia, Pulmonary Artery Hypertension, Ataxia telangiectasia, Shwachman- Diamond syndrome, Mucopolysaccharidosis Type I, Mucopolysaccharidosis Type VI, Mucopolysaccharidosis type III, Niemann-Pick Disease, and Primary Ciliary Dyskinesia. 21. A compound according to any one of clauses 1 to 16, or a pharmaceutical composition according to clause 17, for use in a method of treating conditions or disorders which are associated with a PTC mutation in a subject.BRIEF DESCRIPTION OF THE DRAWINGS

[0133] Embodiments of the invention are further described hereinafter with reference to the accompanying drawings, in which: Figure 1 shows the effect on truncated and full-length (FL) p53 expression upon treatment of HDQ-P1 cells with Example 5 (0.03-80 µM) and also the effect on p21 expression upon treatment of HDQ-P1 cells with Example 5 (33 µM) compared to DMSO (0.3%), and G418 (200 μM). Figure 2 shows the effect of the treatment of Col7a1 R578X transiently transfected HEK293 cells with Example 5 (10-50 μM) compared to DMSO (1%), and G418 (200 μM). These data are normalised to the effect of G418 (200 μM). Figure 3 shows the effect of the treatment of Col7a1 R137X stably transfected HEK293 cells with Example 5 (10-30 μM) compared to DMSO (1%), and G418 (200 μM). These data are normalised to the effect of G418 (200 μM). DETAILED DESCRIPTION

[0134] The term Cm-Cn refers to a group with m to n carbon atoms. For the absence of doubt, the term “C0” refers to a group with 0 carbon atoms.

[0135] The term “alkyl” refers to a monovalent linear or branched saturated hydrocarbon chain. For example, C1-C6-alkyl may refer to methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec- butyl, tert-butyl, n-pentyl and n-hexyl. The alkyl groups may be unsubstituted or substituted by one or more substituents.

[0136] The term “alkylene” refers to a bivalent linear saturated hydrocarbon chain. For example, C1-C3-alkylene may refer to methylene, ethylene or propylene. The alkylene groups may be unsubstituted or substituted by one or more substituents. For the absence of doubt, the term “C0-alkylene” refers to a group in which an alkylene chain is absent. For example, “C0-alkylene-Ra” refers to an Ra.

[0137] The term “haloalkyl” refers to a hydrocarbon chain substituted with at least one halogen atom independently chosen at each occurrence from: fluorine, chlorine, bromine and iodine. The halogen atom may be present at any position on the hydrocarbon chain. For example, C1-C6-haloalkyl may refer to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl e.g. 1-chloromethyl and 2-chloroethyl, trichloroethyl e.g. 1,2,2-trichloroethyl, 2,2,2- trichloroethyl, fluoroethyl e.g. 1-fluoromethyl and 2-fluoroethyl, trifluoroethyl e.g. 1,2,2- trifluoroethyl and 2,2,2-trifluoroethyl, chloropropyl, trichloropropyl, fluoropropyl, trifluoropropyl. A haloalkyl group may be a fluoroalkyl group, i.e. a hydrocarbon chain substituted with at leastone fluorine atom. Thus, a haloalkyl group may have any amount of halogen substituents. The group may contain a single halogen substituent, it may have two or three halogen substituents, or it may be saturated with halogen substituents.

[0138] The term “alkenyl” refers to a branched or linear hydrocarbon chain containing at least one double bond. The double bond(s) may be present as the E or Z isomer. The double bond may be at any possible position of the hydrocarbon chain. For example, “C2-C6-alkenyl” may refer to ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl. The alkenyl groups may be unsubstituted or substituted by one or more substituents.

[0139] The term “alkynyl” refers to a branched or linear hydrocarbon chain containing at least one triple bond. The triple bond may be at any possible position of the hydrocarbon chain. For example, “C2-C6-alkynyl” may refer to ethynyl, propynyl, butynyl, pentynyl and hexynyl. The alkynyl groups may be unsubstituted or substituted by one or more substituents.

[0140] The term “cycloalkyl” refers to a saturated hydrocarbon ring system containing 3, 4, 5 or 6 carbon atoms. For example, “C3-C6-cycloalkyl” may refer to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. The cycloalkyl groups may be unsubstituted or substituted by one or more substituents.

[0141] The term “y- to z-membered heterocycloalkyl” refers to a y- to z- membered heterocycloalkyl group. Thus it may refer to a monocyclic or bicyclic saturated group having from y to z atoms in the ring system and comprising 1 or 2 heteroatoms independently selected from O, S and N in the ring system (in other words 1 or 2 of the atoms forming the ring system are selected from O, S and N). Examples of heterocycloalkyl groups include; piperidine, piperazine, morpholine, thiomorpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, dihydrofuran, tetrahydropyran, dihydropyran, dioxane, azepine. A heterocycloalkyl group may be unsubstituted or substituted by one or more substituents. Heterocycloalkyl groups may be monocyclic. Heterocycloalkyl groups may be bicyclic. Bicyclic heterocycloalkyl groups may be fused, spirofused or bridged groups. The term “heterocycloalkyl fused to a phenyl ring” may mean bicyclic ring systems in which one ring of the bicyclic ring system is phenyl and the other ring is a saturated heterocycloalkyl rin For exam le the term “heterocycloalkyl fusedto a phenyl ring” may refer to the group: , e.g., a 5-membered heterocycloalkyl group fused to a phenyl ring.

[0142] Aryl groups may be any aromatic carbocyclic ring system (i.e. a ring system containing 2(2n + 1)π electrons). Aryl groups may have from 6 to 10 carbon atoms in the ring system. Aryl groups will typically be phenyl groups. Aryl groups may be naphthyl groups or biphenyl groups.

[0143] The term ‘heterocyclyl’ group refers to rings comprising from 1 to 4 heteroatoms independently selected from O, S and N. The rings may be heterocycloalkyl rings (including both saturated and partially saturated rings) or heteroaryl rings. The term “heterocyclyl” also encompasses groups that are tautomers of hydroxy heteroaryl groups, such pyridones, and tautomers of hydroxy heteroaryl groups that are substituted on the nitrogen, such as N-alkyl pyridones.

[0144] The term ‘heterocycloalkenyl’ refers to partially saturated rings comprising from 1 to 2 heteroatoms independently selected from O, S and N. The term “heterocycloalkenyl fused to a phenyl ring” may mean bicyclic ring systems in which one ring of the bicyclic ring system is phenyl and the other ring is a partially saturated heterocycloalkenyl ring.

[0145] The term “heteroaryl” refers to any aromatic (i.e. a ring system containing 2(2n + 1)π electrons) ring system comprising from 1 to 4 heteroatoms independently selected from O, S and N (in other words from 1 to 4 of the atoms forming the ring system are selected from O, S and N). Thus, any heteroaryl groups may be independently selected from: 5 membered heteroaryl groups in which the heteroaromatic ring is substituted with 1-4 heteroatoms independently selected from O, S and N; and 6-membered heteroaryl groups in which the heteroaromatic ring is substituted with 1-3 (e.g.1-2) nitrogen atoms. Specifically, heteroaryl groups may be independently selected from: pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, triazole, oxadiazole, thiadiazole, tetrazole; pyridine, pyridazine, pyrimidine, pyrazine, triazine, quinoline, isoquinoline, indole, benzofuran, benzopyrazole, benzimidazole.

[0146] Compounds of the invention containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of the invention contains a double bond such as a C=C or C=N group, geometric cis / trans (or Z / E) isomers are possible. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism (‘tautomerism’) can occur. This can take the form of proton tautomerism in compounds of the invention containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.

[0147] Included within the scope of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of the invention, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts wherein the counter ion is optically active, for example, d-lactate or l-lysine, or racemic, for example, dl-tartrate or dl-arginine.

[0148] Cis / trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.

[0149] Conventional techniques for the preparation / isolation of individual enantiomers when necessary include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). Thus, chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and for specific examples, 0 to 5% by volume of an alkylamine e.g. 0.1% diethylamine. Concentration of the eluate affords the enriched mixture.

[0150] Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of the invention contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography and / or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.

[0151] Throughout the specification, a down or up wedge bond (i.e. or ) is used to depict absolute configuration. Where a down or up wedge bond is used at a particular position, the compound has substantially a single configuration (either R or S) at the indicated position.A down or up rectangular bond (i.e. or ) is used to depict relative stereochemistry between two positions. Where a down or up rectangular bond is used at a chiral centre, the compound is in the form of a mixture (typically a 1:1 mixture) of R and S configurations at the indicated position.

[0152] When any racemate crystallises, crystals of two different types are possible. The first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. The second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.

[0153] While both of the crystal forms present in a racemic mixture have identical physical properties, they may have different physical properties compared to the true racemate. Racemic mixtures may be separated by conventional techniques known to those skilled in the art - see, for example, “Stereochemistry of Organic Compounds” by E. L. Eliel and S. H. Wilen (Wiley, 1994).

[0154] Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, malic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benzenesulphonic, salicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids. Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts.

[0155] Compounds and salts described in this specification may be isotopically-labelled (or “radio-labelled”). Accordingly, one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of radionuclides that may be incorporated include2H (also written as “D” for deuterium),3H (also written as “T” for tritium),11C,13C,14C,15O,17O,18O,13N,15N,18F,36Cl,123I,25I,32P,35S and the like. The radionuclide that is used will depend on the specific application of that radio-labelled derivative. For example, for in vitro competition assays,3H or14C are often useful. For radio-imaging applications,11C or18F are often useful. In some embodiments, the radionuclide is3H. In some embodiments, the radionuclide is14C. In some embodiments, the radionuclide is11C. And in some embodiments, the radionuclide is18F.

[0156] Isotopically-labelled compounds can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described using an appropriate isotopically-labelled reagent in place of the non-labelled reagent previously employed.

[0157] The selective replacement of hydrogen with deuterium in a compound may modulate the metabolism of the compound, the PK / PD properties of the compound and / or the toxicity of the compound. For example, deuteration may increase the half-life or reduce the clearance of the compound in vivo. Deuteration may also inhibit the formation of toxic metabolites, thereby improving safety and tolerability. It is to be understood that the inventionencompasses deuterated derivatives of compounds of formula (I). As used herein, the term deuterated derivative refers to compounds of the invention where in a particular position at least one hydrogen atom is replaced by deuterium. Accordingly, in a compound of the invention one or more hydrogen atom is optionally replaced by deuterium. For example, one or more hydrogen atoms in a C1-4-alkyl group may be replaced by deuterium to form a deuterated C1-4-alkyl group. By way of example, if any of R2a, R2b, R3, R4, R5, R6, R7, R7a, R7b, R8, R8a, R9, or R10is methyl, the invention also encompasses -CD3, -CHD2and -CH2D. Similarly R2a, R2b, R3, R4, R5, R6, R7, R7a, R8, or R8amay be D.

[0158] The activity of the compounds of the present invention can be assessed by a variety of in silico, in vitro and in vivo assays. In silico analysis of a variety of compounds has been demonstrated to be predictive of ultimate in vitro and even in vivo activity.

[0159] It is to be appreciated that references to “treating” or “treatment” include prophylaxis as well as the alleviation of established symptoms of a condition. “Treating” or “treatment” of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

[0160] A “therapeutically effective amount” includes the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to affect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.

[0161] A compound of the invention, or pharmaceutically acceptable salt thereof, may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the compounds of the invention, or pharmaceutically acceptable salt thereof, is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

[0162] Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.

[0163] Depending on the mode of administration of the compounds of the invention, the pharmaceutical composition which is used to administer the compounds of the invention willpreferably comprise from 0.05 to 99 % w / w compounds of the invention, more preferably from 0.05 to 80 % w / w compounds of the invention, still more preferably from 0.10 to 70 % w / w compounds of the invention, and even more preferably from 0.10 to 50 % w / w compounds of the invention (all percentages by weight being based on total composition).

[0164] The pharmaceutical compositions may be administered topically (e.g. to the skin) in the form, e.g., of creams, ointments, gels, lotions, solutions, suspensions; or systemically, e.g. by oral administration in the form of tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs; or by parenteral administration in the form of a sterile aqueous or oily solution, suspension or emulsion for injection (including intravenous, intracoronary, subcutaneous, intramyocardial, intraperitoneal, intramuscular, intravascular or infusion); by rectal administration in the form of suppositories or enemas; by inhalation for example as a finely divided powder or a liquid aerosol; or for administration by insufflation (for example as a finely divided powder).

[0165] For oral administration the compounds of the invention may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and / or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide. Alternatively, the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and / or preservative agents.

[0166] For the preparation of soft gelatine capsules, the compounds of the invention may be admixed with, for example, a vegetable oil or polyethylene glycol. Hard gelatine capsules may contain granules of the compound using either the above-mentioned excipients for tablets. Also liquid or semisolid formulations of the compound of the invention may be filled into hard gelatine capsules. Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain colouring agents, flavouring agents, sweetening agents (such as saccharine), preservative agents and / or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.

[0167] For intravenous (parenteral) administration the compounds of the invention may be administered as a sterile aqueous or oily solution.

[0168] The size of the dose for therapeutic or prophylactic purposes of a compound of the invention will naturally vary according to the nature and severity of the conditions, the concentration of the compound required for effectiveness in isolated cells, the concentration of the compound required for effectiveness in experimental animals, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.

[0169] Dosage levels, dose frequency, and treatment durations of compounds of the invention are expected to differ depending on the formulation and clinical indication, age, and co-morbid medical conditions of the patient.

[0170] An effective amount of a compound of the present invention for use in therapy of a condition is an amount sufficient to achieve symptomatic relief in a warm-blooded animal, particularly a human of the symptoms of the condition, to mitigate the physical manifestations of the condition, or to slow the progression of the condition.

[0171] The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.

[0172] For the above-mentioned compounds of the invention the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. In using a compound of the invention for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, a daily dose selected from 0.1 mg / kg to 100 mg / kg, 1 mg / kg to 75mg / kg, 1 mg / kg to 50 mg / kg, 1 mg / kg to 20 mg / kg or 5 mg / kg to 10 mg / kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous or intraperitoneal administration, a dose in the range, for example, 0.1 mg / kg to 30 mg / kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 0.05 mg / kg to 25 mg / kg body weight will be used. Suitably the compound of the invention is admistered orally, for example in the form of a tablet, or capsule doasage form. The daily dose administered orallymay be, for example a total daily dose selected from 1 mg to 1000 mg, 5 mg to 1000 mg, 10 mg to 750 mg or 25 mg to 500 mg. Typically, unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention.

[0173] The compounds of the invention may be administered along with other active compounds as part of a treatment regime. The other active compounds may be administered simultaneously with, subsequently to or previously to the administration of the compounds of the invention. It may be that the pharmaceutical formulation comprising the compounds of the invention also comprises one or more other active compounds. The other active compounds may be anticancer, anti-inflammatory, antibacterial, antiviral, antiemetic, antithrombotic or compounds that alter the metabolism.

[0174] The other active compound may be an aminoglycoside. The other active compound may be an eRF1 modulator. The other active compound may be an inhibitor or suppressor of nonsense mediated decay. The other active compound may be an SMG1 kinase inhibitor. The other active compound may be a ribosomal binder.

[0175] The compounds of the invention may be administered in combination with an aminoglycoside. In some embodiments, the compounds of the invention may allow translational read-through of PTC mutations when administered in combination with a sub- effective, sub-optimal, or sub-maximal amount of an aminoglycoside.

[0176] Aminoglycosides are compounds that have an amino-modified glycoside. Aminoglycosides are compounds that have an amino-modified glycoside. Aminoglycosides may allow translational read-through of PTC mutations. In some embodiments, when a compound of the invention is administered in combination with an aminoglycoside, the aminoglycoside may increase ribosomal read-through of mRNA transcripts carrying a PTC mutation of the cystic fibrosis CFTR channel.

[0177] Non-limiting examples of aminoglycosides include kanamycin A, amikacin, tobramycin, dibekacin, gentamicin, geneticin, sisomicin, netilmicin, neomycin B, neomycin C, paromomycin, streptomycin, plazomicin, tobramycin, ELX-02, and pharmaceutically acceptable salts thereof.

[0178] It may be that administering a compound of the invention in combination with an aminoglycoside enhances PTC read-through. It may be that administering a compound of the invention in combination with an aminoglycoside enhances PTC read-through whilst reducing the dose of aminoglycoside administered, relative to administration of the aminoglycoside alone, thereby reducing side effects, e.g. toxicity, associated with the aminoglycoside.

[0179] It may be that administering a compound of the invention in combination with an aminoglycoside increases the potency and / or beneficial effects of the aminoglycoside.

[0180] It may be that administering a compound of the invention in combination with an aminoglycoside reduces the dose of aminoglycoside required by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more, compared to administration of the aminoglycoside alone.

[0181] The compounds of the invention may be administered in combination with an eRF1 modulator, such as SRI-41315.

[0182] The compounds of the invention may be administered in combination with an inhibitor or suppressor of nonsense mediated decay, such as amlexanox, or NMD1.

[0183] The compounds of the invention may be administered in combination with an SMG1 kinase inhibitor, such as SMG1i.

[0184] The compounds of the invention may be administered in combination with an ribosomal binder, such as ZKN-013.

[0185] The compounds of the invention may be administered in combination with an antibody, for example a checkpoint inhibitor antibody. In some embodiments, the compounds of the invention may allow increased immune-cell recognition of cancer cells for use in the treatment of cancer, when administered in combination with a checkpoint inhibitor antibody. In some embodiments, the compounds of the invention may allow increased immune-cell recognition of cancer cells for use in the treatment of cancer, when administered in combination with a sub-effective, sub-optimal, or sub-maximal amount of a checkpoint inhibitor antibody.

[0186] Checkpoint inhibitor antibodies are a type of immunotherapy in oncology. Checkpoint inhibitor antibodies recognise and block different checkpoint proteins, for example, CTLA-4, PD-1 and PD-L1, which triggers immune recognition and destruction of a tumour. Immune recognition may be enhanced when a compound of the invention is administered in combination with a checkpoint inhibitor antibody, wherein the compound promotes read- through of PTCs and increases the expression of neoantigens in cancer cells.

[0187] Non-limiting examples of checkpoint inhibitor antibodies include pembrolizumab, nivolumab, cemiplimab, atezolizumab, durvalumab, avelumab, relatlimab, and ipilimumab.

[0188] It may be that administering a compound of the invention in combination with a checkpoint inhibitor antibody increases the potency and / or beneficial effects of the checkpoint inhibitor antibody.

[0189] Throughout the description and claims of this specification, the words “comprise” and “contain” and variations of them mean “including but not limited to”, and they are not intended to (and do not) exclude other moieties, additives, components, integers or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

[0190] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

[0191] It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the specification appended hereto.

[0192] The reader's attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.

[0193] The compounds of formula (I) can be made according to or analogously to General Schemes 1 to 7 and / or the following Examples. EXAMPLES Table of Abbreviations:(Prep-)HPLC (preparative-) High performance liquid chromatography B B - A D D D D D D D D D E E E E E E E F F h H H H H H L m N N N N P P Pchloropyridine κN)palladiumPd-PEPPSI-IPentCl 2- (SP-4-1)-[1,3-Bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3- m P P R R R S T T t T T T T T T w X XNMR Methods: 1H NMR spectra are recorded on Bruker AVANCE III HD 300, Bruker AVANCE NEO 400 or Bruker AVANCE III HD 400 spectrometers. Chemical shifts are denoted in ppm (δ) relative to residual protonated solvent as an internal standard as described in, for example, Gottlieb et al. Journal of Organic Chemistry (1997) 627512. The splitting pattern for NMR spectra are denoted as follows: s (singlet), br (broad), d (doublet), t (triplet), m (multiplet) or combinations thereof. Coupling constants (J) are designated in Hz and reported to one decimal place. Purification Methods: Liquid chromatography-mass spectra (LCMS) are recorded using the following systems and running conditions: n- - . . . 90 - - 5 1.20 0.60 1.5 X90 30 2.00 5 0.10 0.7 1.5 Zm cetontre / 0.07%FA30 mm × A B C D Emm, . µm Acetonitrile 98 20 4 98 0.01 0.19 1.5 Library FHALO AQ- 98 5 2.2 98 0.01 0.19 1.5 Library G H I J KPurification by preparative HPLC (prep-HPLC) employs the following instruments and conditions: Fi l i nPhenyl OBD Water 98 88 60 10 AZColumn 19 x (0.05% TFA)g, - μ NH3·H2O) / ACN Separation by SFC employs the following instruments and conditions: nson euose- He ar rary B 5 µm x:DCMB: EtOHSeparation by Chiral-HPLC employs the following instruments and conditions: I i i l Fi l G diProcess for Preparation:

[0194] Certain compounds of the invention may be synthesised according to the general methods disclosed herein. Certain compounds of the invention may be synthesised according to general schemes 1 to 7. Certain compounds of the invention may be synthesised according to or analogously to the syntheses provided in the examples. General Scheme 1

[0195] General Scheme 1 illustrates a route to compounds of Formula (I) and is described in the following examples.

[0196] Appropriately functionalised starting materials can be activated into a suitable leaving group X1(where X1= Cl, Br, OMs, OTs, OTf) by use of conditions well-known to those skilled in the art such as, for example, POCl3, POBr3, triflic anhydride, mesyl chloride or tosyl chloridein the presence of a suitable base if necessary (for example TEA, DIPEA), in a suitable solvent (for example DCM, THF) if necessary, with heating if required.

[0197] Sequential displacement of X1can be achieved by reacting an amine in a cross- coupling reaction (where X1is, for example, Cl, Br, OTf) in the presence of a suitable catalyst (for example palladium(II) acetate, Brettphos Pd G3, Pd2(dba)3), with a ligand if necessary (for example, Brettphos, XantPhos) with a suitable base (for example Na2CO3, Cs2CO3) in a suitable solvent (for example 1,4-dioxane, toluene, THF) with heating (conventional or by microwave irradiation) if required.

[0198] Alternatively, sequential displacement of X1can be achieved by reacting an amine in a substitution reaction (where X1is, for example, Cl, OMs, OTs) conducted in the presence of a suitable base (for example TEA, KF, CsF, potassium tert-butoxide, Na2CO3, Cs2CO3) in a suitable solvent (for example 1,4-dioxane, DMSO, THF, NMP, or neat conditions) with heating (conventional or by microwave irradiation) if required.

[0199] It will be well understood by those skilled in the art that either two coupling reactions, two substitution reactions or a mixture of coupling and substitution reactions may be required for the sequential, regioselective displacement of both X1groups. General Scheme 2

[0200] General Scheme 2 illustrates a route to compounds of Formula (III) and is described in the following examples.

[0201] A cross-coupling reaction of suitably functionalised Intermediates A (where X2is, for example, Cl, Br, I, OSO2CF3) with cyanamide can be conducted in the presence of a suitable catalyst (for example palladium(II) acetate, Brettphos Pd G3, Pd2(dba)3), with a ligand if necessary (for example, Brettphos, XantPhos) with a suitable base (for example Na2CO3, Cs2CO3) in a suitable solvent (for example 1,4-dioxane, toluene, THF) with heating (conventional or by microwave irradiation) if required.

[0202] Alternatively, a nucleophilic aromatic substitution (SNAr) reaction of suitably functionalised Intermediates A (where X2is, for example, F, Cl, OMs, OTs) with cyanamide can be conducted in the presence of a suitable base (for example TEA, KF, CsF, potassiumtert-butoxide, Na2CO3, Cs2CO3) in a suitable solvent (for example 1,4-dioxane, DMSO, THF, NMP, or neat conditions) with heating (conventional or by microwave irradiation) if required.

[0203] The resultant cyano-cyanamide product can be cyclised by reaction with an appropriate nucleophile (for example an amine or hydroxylamine), using an appropriate base if necessary (for example triethylamine, DIPEA, potassium carbonate), in an appropriate solvent (for example DCM, DMSO, DMF, NMP, THF, 1,4-dioxane, ethanol, methanol) with heating (conventional or by microwave irradiation) if required. General Scheme 3

[0204] Intermediates A may be commercially available; synthesised using methods similar to those previously described in, for example, WO2005097750 A1, CN109232412 A or WO2013089573 A1; or according to General Scheme 3 and as described in the following examples.

[0205] A condensation of suitably functionalised 1,3-diadehydes or ketones with 2- cyanoacetamide may be carried out in the presence of a suitable base (for example, piperidine, sodium hydride) in a suitable solvent (for example, ethanol, DMSO) with heating if required.

[0206] The resultant pyrimidone intermediates can be activated into a suitable leaving group X2(where X2is, for example, F, Cl, Br, I, OMs, OTs, OTf) by use of conditions well-known to those skilled in the art such as, for example, POCl3, POBr3, triflic anhydride, mesyl chloride or tosyl chloride in the presence of a suitable base if necessary (for example TEA, DIPEA), in a suitable solvent (for example DCM, THF) if necessary, with heating if required.

[0207] It will be appreciated by those skilled in the art that the condensation step may result in mixture of isomers in varying ratios which may be separated using well-known techniques (for example, crystallisation, normal, reverse and super-critical fluid chromatography). Separation may be conducted after the condensation step, or after activation of the crude mixture. General Scheme 4

[0208] Alternatively, Intermediates B may be synthesised according to General Scheme 4.

[0209] A nucleophilic aromatic substitution (SNAr) reaction of suitably functionalised starting material (where X4is, for example, F, Cl and X3is, for example, Br, I) with cyanamide can be conducted in the presence of a suitable base (for example TEA, KF, CsF, potassium tert- butoxide, Na2CO3, Cs2CO3) in a suitable solvent (for example 1,4-dioxane, DMSO, THF, NMP, or neat conditions) with heating (conventional or by microwave irradiation) if required.

[0210] A cross-coupling reaction of suitably functionalised starting material (where X4is, for example, I, and X3is, for example, Cl, Br) with cyanamide can be conducted in the presence of a suitable catalyst (for example palladium(II) acetate, Brettphos Pd G3, Pd2(dba)3), with a ligand if necessary (for example, Brettphos, XantPhos) with a suitable base (for example Na2CO3, Cs2CO3) in a suitable solvent (for example 1,4-dioxane, toluene, THF) with heating (conventional or by microwave irradiation) if required.

[0211] The cyano group can be introduced into the resultant intermediates by way of a Negishi coupling using, for example, zinc cyanide in the presence of a suitable palladium catalyst (for example Pd2dba3) with a suitable ligand (for example triphenylphosphine or BINAP) and in a suitable solvent (for example 1,4-dioxane) with heating if necessary. General Scheme 5

[0212] General Scheme 5 illustrates a route to compounds of Formula (II) and is described in the following examples.

[0213] Appropriately substituted starting materials can be cyclised to furnish Intermediates C using, for example, potassium cyanate with ammonium chloride in water with heating ifnecessary, as described in, for example, WO2006090167 A2 or Bioorganic & Medicinal Chemistry Letters (2009), 19(20), 5950-5953.

[0214] Alternatively, appropriately substituted starting materials can be cyclised to furnish Intermediates C using, for example, urea (neat or in a suitable solvent such as water, for example), in the presence of sodium hydroxide if necessary, with heating if necessary, as described in, for example, Tetrahedron (2012), 68(43), 8908-8915; Journal of Medicinal Chemistry (2016), 59(4), 1370-1387; US20070281949 A1 or WO2005049033 A1.

[0215] The resultant intermediates can be activated into a suitable leaving group X5(where X5= Cl, Br, OMs, OTs, OTf) by use of conditions well-known to those skilled in the art such as, for example, POCl3, POBr3, triflic anhydride, mesyl chloride or tosyl chloride in the presence of a suitable base if necessary (for example TEA, DIPEA), in a suitable solvent (for example DCM, THF) if necessary, with heating if required.

[0216] Sequential displacement of X5can be achieved by reacting an amine in a cross- coupling reaction (where X5is, for example, Cl, Br, OTf) in the presence of a suitable catalyst (for example palladium(II) acetate, Brettphos Pd G3, Pd2(dba)3), with a ligand if necessary (for example, Brettphos, XantPhos) with a suitable base (for example Na2CO3, Cs2CO3) in a suitable solvent (for example 1,4-dioxane, toluene, THF) with heating (conventional or by microwave irradiation) if required.

[0217] Alternatively, sequential displacement of X5can be achieved by reacting an amine in a substitution reaction (where X5is, for example, Cl, OMs, OTs) conducted in the presence of a suitable base (for example TEA, KF, CsF, potassium tert-butoxide, Na2CO3, Cs2CO3) in a suitable solvent (for example 1,4-dioxane, DMSO, THF, NMP, or neat conditions) with heating (conventional or by microwave irradiation) if required.

[0218] It will be well understood by those skilled in the art that either two coupling reactions, two substitution reactions or a mixture of coupling and substitution reactions may be required for the sequential, regioselective displacement of both X5groups. General Scheme 6

[0219] Alternatively, Intermediates C may be synthesised according to General Scheme 6 and as described in the following Examples.

[0220] An appropriate dicarbonyl starting material can be condensed with a suitable amidine ester (for example ethyl 3-amino-3-iminopropanoate as a free base or salt, for example hydrochloride) in the presence of a suitable base (for example piperidine, DIPEA, TEA, potassium tert-butoxide, Na2CO3, sodium hydroxide, pyridine) in a suitable solvent (for example methanol, ethanol, isopropanol, dichloroethane, acetonitrile, 1,4-dioxane, tetrahydrofuran, toluene, DMF, DMSO) with heating (conventional or by microwave irradiation) if required.

[0221] It will be appreciated by those skilled in the art that the condensation step may result in mixture of isomers in varying ratios which may be separated using well-known techniques (for example, crystallisation, normal, reverse and super-critical fluid chromatography).

[0222] The resultant amino group can be activated with a suitable isocyanate (for example 2,2,2-trichloroacetyl isocyanate) in a suitable solvent (for example dichloroethane, 1,4- dioxane, tetrahydrofuran, toluene) with heating (conventional or by microwave irradiation) if required.

[0223] The resultant compound can be cyclised in the presence of ammonia in a suitable solvent (for example methanol, ethanol, isopropanol) with heating (conventional or by microwave irradiation) if required, under pressure if required. General Scheme 7

[0224] Alternatively, Intermediates C may be synthesised according to General Scheme 7 and as described in the following Examples.

[0225] An appropriate starting material (for example, 6-aminouracil) can be condensed with a suitable diketone (for example acetylacetone) in the presence of a suitable acid (for example polyphosphoric acid) with heating (conventional or by microwave irradiation) if required.

[0226] It will be appreciated by those skilled in the art that the condensation step may result in mixture of isomers in varying ratios which may be separated using well-known techniques (for example, crystallisation, normal, reverse and super-critical fluid chromatography). Example 1: N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamineRoute A Preparation 1 – 2-(cyanoamino) pyridine-3-carbonitrile To a solution of 2-chloropyridine-3-carbonitrile (1.00 g, 7.22 mmol) in NMP (10.0 mL) at room temperature was added cyanamide, monosodium salt (690 mg, 10.8 mmol). The mixture was stirred at 60 °C overnight. The mixture was directly purified by silica gel column chromatography (eluted with EtOAc / MeOH (from 0 to 100%)) to afford the title compound as a yellow solid (1.0 g, crude). LCMS: m / z = 145 [M+H]+. Preparation 2 – N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamine To a solution of 2-(cyanoamino) pyridine-3-carbonitrile (600 mg, 4.16 mmol) in 1,4-dioxane (10.0 mL) at room temperature was added 1-methylpiperidin-4-amine (570 mg, 5.00 mmol). The mixture was stirred at 100 °C overnight. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLCGto afford the title compound as a yellow solid (30.7 mg, 2.8%).1H NMR (400 MHz, DMSO-d6) δ 8.62 - 8.56 (m, 1H), 8.36 - 8.30 (m, 1H), 7.39 (br, 2H), 6.98 (s, 1H), 6.56 (br, 1H), 3.87 - 3.73 (m, 1H), 2.79 - 2.70 (m, 2H), 2.16 (s, 3H), 1.99 - 1.89 (m, 2H), 1.86 - 1.78 (m, 2H), 1.58 - 1.44 (m, 2H). LCMSB: m / z = 259 [M+H]+. Route B Preparation 3 – 2-chloropyrido[2,3-d]pyrimidin-4-amine Into a 40 mL vial were added 2,4-dichloropyrido[2,3-d]pyrimidine (500 mg, 2.50 mmol) and ammonium hydroxide (5.0 mL) at room temperature. The resulting mixture was stirred overnight at 80 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with MtBE (8.0 mL). This resulted in title compound as a light-yellow solid (430 mg, crude). LCMS m / z = 181 [M+H+] Preparation 4 – N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamine To a stirred solution of 2-chloropyrido[2,3-d]pyrimidin-4-amine (200 mg, 1.11 mmol) in DMSO (5.0 mL) was added Cs2CO3 (721 mg, 2.21 mmol) and 1-methylpiperidin-4-amine (252 mg, 2.21 mmol) in portions at room temperature. The resulting mixture was stirred at 100 °C for 12 h. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered through a short pad of Celite. The combined filtrate was purified by Prep-HPLCAStoafford the title compound as a light yellow solid (5 mg, 1.7%).1H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 3.6 Hz, 1H), 8.36-8.33 (m, 1H), 7.38 (br., 2H), 6.97 (s, 1H), 6.66 (br s, 1H), 3.91 – 3.64 (m, 1H), 2.75-2.70 (m, 2H), 2.16 (s, 3H), 2.00 – 1.89 (m, 2H), 1.81-1.80 (m, 2H), 1.51- 1.50 (m, 2H). LCMSHm / z = 259 [M+H+] Example 2: 5-methyl-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diaminePreparation 5 – N-(3-cyano-4-methylpyridin-2-yl) cyanamide To a stirred solution of 2-chloro-4-methylpyridine-3-carbonitrile (1.00 g, 6.55 mmol) in NMP (20.0 mL) at room temperature was added cyanamide, monosodium salt (840 mg, 13.1 mmol). The resulting mixture was stirred at 60 °C for 1 h. The mixture was acidified to pH=6 with conc. HCl. The resulting mixture was filtered, the filter cake was washed with water (3x3.00 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep- HPLCBto afford the title compound as a white solid (560 mg, 54.0%). LCMS: m / z = 159 [M+H]+. Preparation 6 – 5-methyl-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamine A solution of 2-(cyanoamino)-4-methylpyridine-3-carbonitrile (200 mg, 1.27 mmol) and 1- methylpiperidin-4-amine (0.19 mL, 1.52 mmol) in EtOH (4.00 mL) was stirred at 80 °C for 6 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLCC. The residue was purified by trituration with MTBE (10.0 mL) to afford the title compound as white solid (100.4 mg, 29.2%).1H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 7.00 – 6.33 (m, 4H), 3.85 - 3.72 (m, 1H), 2.74 - (d, J = 11.1 Hz, 2H), 2.68 (s, 3H), 2.16 (s, 3H), 2.00 - 1.86 (m, 2H), 1.89 - 1.81 (m, 2H), 1.56 - 1.46 (m 2H). LCMSA: m / z = 273 [M+H]+. Example 3: 7-methyl-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diaminePreparation 7 – N-(3-cyano-6-methylpyridin-2-yl)cyanamide To a mixture of 2-chloro-6-methylpyridine-3-carbonitrile (1.00 g, 6.55 mmol) in NMP (10.0 mL) was added cyanamide, monosodium salt (839 mg, 13.1 mmol). The mixture was stirred at 60°C overnight. The resulting mixture was diluted with water (30.0 mL) and acidified to pH 6.5 by the addition of aq. HCl (1.0 M). The product was precipitated, filtered and dried to afford the title compound as a yellow solid (555.4 mg, 53.6%). LCMS: m / z = 159 [M+H]+. Preparation 2: 7-methyl-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamine To a mixture of 2-(cyanoamino)-6-methylpyridine-3-carbonitrile (300 mg, 1.90 mmol, 1.00 equiv) in EtOH (10.0 mL) was added 1-methylpiperidin-4-amine (0.28 mL, 2.28 mmol, 1.20 equiv). The mixture was stirred at 80 °C overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLCE. The product was further purified by trituration with MTBE (10 mL) to afford the title compound as a light-yellow solid (81 mg, 15.9%).1H NMR (300 MHz, DMSO-d6) δ 8.22 (d, J = 8.1 Hz, 1H), 7.29 (br, 2H), 6.88 (d, J = 8.1 Hz, 1H), 6.50 (br, 1H), 3.87 - 3.64 (m, 1H), 2.82 - 2.62 (m, 2H), 2.45 (s, 3H), 2.16 (s, 3H), 2.00 - 1.88 (m, 2H), 1.81 - 1.73 (m, 2H), 1.53 - 1.49 (m, 2H). LCMSA: m / z = 273 [M+H]+. Example 4: 6-methyl-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diaminePreparation 8 – N-(3-cyano-5-methylpyridin-2-yl) cyanamide To a solution of 2-chloro-5-methylpyridine-3-carbonitrile (400 mg, 2.62 mmol) in DMSO (4.0 mL) at room temperature was added cyanamide, monosodium salt (252 mg, 3.93 mmol). The mixture was stirred at 60 °C for 2 h. The reaction was quenched with water. The mixture was acidified to pH 6 with aq. HCl (1M). The precipitated solids were collected by filtration and washed with EtOAc (3 x 30 mL). The crude product was further purified by trituration with MTBE (5.0 mL). The precipitated solids were dried under vacuum to afford the title compound as a grey solid (390 mg, 94.1%). LCMS: m / z = 159 [M+H]+. Preparation 2: 6-methyl-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamine To a stirred solution of 2-(cyanoamino)-5-methylpyridine-3-carbonitrile (100 mg, 0.632 mmol, 1.00 equiv) in EtOH (2.0 mL) at room temperature was added 1-methylpiperidin-4-amine (86.6 mg, 0.758 mmol, 1.20 equiv). The mixture was stirred at 80 °C overnight. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep- HPLCEto afford the title compound as a white solid (29.6 mg, 16.5%).1H NMR (400 MHz, MeOD) δ 8.49 (s, 1H), 8.13 (s, 1H), 4.02 - 3.92 (m, 1H), 2.86 (d, J = 11.7 Hz, 2H), 2.38 (s,3H), 2.30 (s, 3H), 2.27 - 2.17 (m, 2H), 2.09 - 2.01 (m, 2H), 1.66 - 1.53 (m, 2H). LCMSB: m / z = 273 [M+H]+. Example 5: 5,7-dimethyl-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4- diamineRoute A Preparation 9 – 2-(cyanoamino)-4,6-dimethylpyridine-3-carbonitrile To a stirred mixture of 2-chloro-4,6-dimethylpyridine-3-carbonitrile (30.0 g, 180 mmol) in DMSO (300 mL) at room temperature was added cyanamide, monosodium salt (22.7 g, 360 mmol). The resulting mixture was stirred at 60 °C for 2 h. The reaction was quenched by the addition of water (600 mL). The residue was acidified to pH 6 with aq. HCl (1 M). The precipitated solids were collected by filtration and washed with MTBE (3 x 100 mL). The filter cake was dried under vacuum to afford the title compound as a brown solid (25.0 g, crude). LCMS: m / z = 173 [M+H]+. Preparation 10 – 5,7-dimethyl-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamine To a stirred mixture of 2-(cyanoamino)-4,6-dimethylpyridine-3-carbonitrile (20.0 g, 116 mmol) in EtOH (400 mL) at room temperature was added 1-methylpiperidin-4-amine (15.9 g, 139 mmol) dropwise. The resulting mixture was stirred at 80 °C overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLCAand the product was triturated with MTBE (50 mL) to afford the title compound as a brown solid (10.6 g, 31.6%).1H NMR (300 MHz, DMSO-d6) δ 6.67 (s, 3H), 6.38 (s, 1H), 3.84 - 3.69 (m, 1H), 2.74 (d, J = 11.6 Hz, 2H), 2.63 (s, 3H), 2.37 (s, 3H), 2.16 (s, 3H), 2.02 - 1.88 (m, 2H), 1.81 - 1.78 (m, 2H), 1.56 - 1.48 (m, 2H). LCMSA: m / z = 287 [M+H]+. Route B Preparation 11 – 5,7-dimethylpyrido[2,3-d]pyrimidine-2,4-diol To a stirred mixture of 6-aminouracil (50.0 g, 393 mmol) in acetylacetone (200 mL) at room temperature was added PPA (90.5 g, 786 mmol). The resulting mixture was stirred at 100 °C for 1 h. The mixture was allowed to cool down to room temperature. The reaction was quenched with NaHCO3(aq) at 0 °C. The precipitated solids were collected by filtration and washed with water (2 × 300 mL). The solid was further purified by triturationwith MtBE (300 mL). This resulted in title compound as an off-white solid (38.0 g, crude). LCMS m / z = 192 [M+H]+Preparation 12 – 2,4-dichloro-5,7-dimethylpyrido[2,3-d]pyrimidine To a stirred mixture of 5,7-dimethylpyrido[2,3-d]pyrimidine-2,4-diol (15.5 g, 81.1 mmol) in POCl3(155 mL) at 0 °C was added N,N-diethylaniline (60.5 g, 405 mmol) dropwise. The resulting mixture was stirred at 60 °C for 3 h. The resulting mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The mixture basified to pH 8 with saturated NaHCO3(aq.). The resulting mixture was extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4.After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2:1) to afford the title compound as a yellow solid (9.8 g, 40.2%). LCMS: m / z = 228 [M+H]+Preparation 13 – 2-chloro-5,7-dimethylpyrido[2,3-d]pyrimidin-4-amine A mixture of 2,4-dichloro-5,7-dimethylpyrido[2,3-d]pyrimidine (6.00 g, 26.3 mmol) in ammonium hydroxide (90.0 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLCBto afford title compound as an off-white solid (4.45 g, 81.1%). LCMS m / z = 209 [M+H]+Preparation 14 – 5,7-dimethyl-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamine To a stirred solution of 2-chloro-5,7-dimethylpyrido[2,3-d]pyrimidin-4-amine (60.0 mg, 0.288 mmol,) in dioxane (1.50 mL) at room temperature was added 1-methylpiperidin-4-amine (164 mg, 1.44 mmol). The resulting mixture was stirred at 80 °C overnight. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in DMF (2.00 mL). The crude product was purified by Prep-HPLCAUto afford the title compound as an off-white solid (5.5 mg, 6.52%).1H NMR (400 MHz, DMSO-d6) δ 6.67 (s, 3H), 6.38 (s, 1H), 3.84 - 3.69 (m, 1H), 2.74 (d, J = 11.6 Hz, 2H), 2.63 (s, 3H), 2.37 (s, 3H), 2.16 (s, 3H), 2.02 - 1.88 (m, 2H), 1.81 - 1.78 (m, 2H), 1.56 - 1.48 (m, 2H). LCMSH: m / z = 287 [M+H]+. Example 6: 5,7-dimethyl-N2-(3-morpholinopropyl)pyrido[2,3-d]pyrimidine-2,4-diamineTo a stirred mixture of 2-(cyanoamino)-4,6-dimethylpyridine-3-carbonitrile (100 mg, 0.581 mmol) in EtOH (1.5 mL) at room temperature was added 4-morpholinepropanamine (100 mg, 0.697 mmol). The resulting mixture was stirred at 80 °C overnight. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLCHto afford the title compound as a white solid (79 mg, 42.9%).1H NMR (300 MHz, MeOD) δ 6.78 (s, 1H), 3.70 (t, J = 4.7 Hz, 4H), 3.48 (t, J = 6.7 Hz, 2H), 2.71 (s, 3H), 2.53 - 2.42 (m, 9H), 1.87 -1.77 (m, 2H). LCMSC: m / z = 317 [M+H]+. Example 7: 5,7-dimethyl-N2-(3-(piperidin-1-yl)propyl)pyrido[2,3-d]pyrimidine-2,4- diamineAs described for Example 6, using 3-(piperidin-1-yl) propan-1-amine and purification by Prep- HPLCLto afford the title compound as a white solid (90 mg, 43.5%). 1H NMR (400 MHz, MeOD) δ 6.79 (s, 1H), 3.48 - 3.45 (m, 2H), 2.71 -2.62 (m, 9H), 2.46 (s, 3H), 1.92 - 1.87 (m, 2H), 1.69 – 1.60 (m, 4H).1.60 - 1.51 (m, 2H). LCMSEm / z = 315 [M+H]+. Example 8: 4-(3-((4-amino-5,7-dimethylpyrido[2,3-d]pyrimidin-2- yl)amino)propyl)thiomorpholine 1,1-dioxideAs described for Example 6, using 4-(3-aminopropyl) thiomorpholine 1,1-dioxide and purification by Prep-HPLCJto afford the title compound as a white solid (46.9 mg, 44.3%).1H NMR (400 MHz, MeOD) δ 6.80 (s, 1H), 3.51 (t, J = 6.0 Hz, 2H), 3.14 - 3.08 (m, 4H), 3.01 - 2.96 (m, 4H), 2.72 (s, 3H), 2.63 (t, J = 8.0 Hz, 2H), 2.47 (s, 3H), 1.86 - 1.75 (m, 2H). LCMSA: m / z = 365 [M+H]+Example 9: 6-methyl-N3-(1-methylpiperidin-4-yl)pyrimido[4,5-c]isoquinoline-1,3- diamineRoute A Preparation 15 – 1-methyl-3-oxo-3,4-dihydroisoquinoline-4-carbonitrile and 2-hydroxy-4- methylquinoline-3-carbonitrile To a solution of 1-(2-fluorophenyl)ethanone (25.0 g, 181 mmol) and cyanoacetamide (33.5 g, 398 mmol) in DMSO (250 mL) were added NaH (16.7 g, 416 mmol,, 60% wt in mineral oil) in portions at 0 °C. The resulting mixture was stirred at 80 °C overnight. The mixture was allowed to cool down to room temperature. The mixture was acidified to pH 3 with cold HCl (aq., 1 M). The precipitated solids were collected by filtration and washed with water (3 × 50 mL). The solid was dried under vacuum to afford the title compound (19.0 g, crude) as a yellow solid. The crude product (6.0 g) was further purified by Prep-HPLCBto afford 1-methyl-3-oxo-3,4- dihydroisoquinoline-4-carbonitrile (1.78 g) and 2-hydroxy-4-methylquinoline-3-carbonitrile (756 mg). LCMS m / z = 185 [M+H]+Preparation 16 – 4-cyano-1-methylisoquinolin-3-yl trifluoromethanesulfonate To a stirred solution of 1-methyl-3-oxo-3,4-dihydroisoquinoline-4-carbonitrile (100 mg, 0.543 mmol,) and Et3N (151 µL, 1.09 mmol) in DCM (2.0 mL) was added Tf2O (183 uL, 1.09 mmol) dropwise at 0 °C. The resulting mixture was stirred under nitrogen atmosphere at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 10:1) to afford the title compound (130 mg, 75.7%) as a yellow solid. LCMS: m / z = 315 [M-H]- Preparation 17 – N-(4-cyano-1-methylisoquinolin-3-yl)cyanamide To a stirred solution of 4-cyano-1-methylisoquinolin-3-yl trifluoromethanesulfonate (100 mg, 0.316 mmol) and cyanamide (26.6 mg, 0.632 mmol) in 1,4-dioxane (1.5 mL) were added Xantphos (18.3 mg, 0.032 mmol), Pd2(dba)3 (29.0 mg, 0.032 mmol) and DIEA (110 µL, 0.632 mmol) under nitrogen atmosphere at room temperature. The resulting mixture was stirred under nitrogen atmosphere at 100 °C for 1 h. The mixture was allowed to cool down to room temperature and diluted with water / ice (10 mL). The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford the title compound (45.0 mg, 68.4%) as a yellow solid. LCMS m / z = 209 [M+H]+Preparation 18 – 6-methyl-N3-(1-methylpiperidin-4-yl)pyrimido[4,5-c]isoquinoline-1,3-diamine A solution of N-(4-cyano-1-methylisoquinolin-3-yl)cyanamide (40 mg, 0.192 mmol) and 1- methylpiperidin-4-amine (43.9 mg, 0.384 mmol) in EtOH (1.0 mL) was stirred at 80 °Covernight. The mixture was allowed to cool down to room temperature. The residue was purified by Prep-HPLCBthe title compound (7.70 mg, 10.9%) as a yellow solid formate salt.1H NMR (400 MHz, DMSO-d6) δ 8.51 (d, J = 8.5 Hz, 1H), 8.29 (s, 1H), 8.20 (d, J = 8.2 Hz, 1H), 7.77 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 6.98 (s, 2H), 6.58 (s, 1H), 3.87-3.80 (m, 1H), 2.87 (s, 3H), 2.81 (d, J = 11.6 Hz, 2H), 2.21 (s, 3H), 2.06 (t, J = 10.1 Hz, 2H), 1.92 - 1.82 (m, 2H), 1.61 - 1.46 (m, 2H). LCMSI: m / z = 323 [M+H]+Example 10: 5-methyl-N2-(1-methylpiperidin-4-yl)pyrimido[4,5-b]quinoline-2,4-diamineRoute A Preparation 19 – 2-chloro-4-methylquinoline-3-carbonitrile To a solution of 2-hydroxy-4-methylquinoline-3-carbonitrile (1.00 g, 5.43 mmol, synthesised as described in Example 9, Preparation 15) in 1,4-dioxane (15.0 mL) was added phosphorus oxychloride (8.30 g, 54.3 mmol) dropwise at room temperature. The resulting mixture was stirred at 100 °C for 6 h. The mixture was allowed to cool down to room temperature. The reaction was quenched with sat. NaHCO3(aq.) at 0 °C. The resulting mixture was extracted with CH2Cl2(3 × 100 mL). The combined organic layers were washed with brine (1 × 50 mL), dried over anhydrous Na2SO4filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (1:1)) to afford the title compound (260 mg, 23.6%) as a white solid. LCMS: m / z = 203 [M+H]+Preparation 20 – N-(3-cyano-4-methylquinolin-2-yl)cyanamide To a solution of 2-chloro-4-methylquinoline-3-carbonitrile (230 mg, 1.14 mmol), cyanamide (95.0 mg, 2.27 mmol) in 1,4-dioxane (6.0 mL) were added BrettPhos Pd G3 (103 mg, 0.114 mmol), BrettPhos (61.0 mg, 0.114 mmol) and Cs2CO3 (740 mg, 2.27 mmol). The mixture was stirred at 100 °C under nitrogen atmosphere for 1 h. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with MeOH (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLCBto afford the title compound (129 mg, 54.6%) as a yellow solid. LCMS: m / z = 209 [M+H]+Preparation 21 – 5-methyl-N2-(1-methylpiperidin-4-yl)pyrimido[4,5-b]quinoline-2,4-diamine A mixture of N-(3-cyano-4-methylquinolin-2-yl)cyanamide (110 mg, 0.528 mmol) and 1- methylpiperidin-4-amine (72.0 mg, 0.634 mmol) in 1,4-dioxane (2.5 mL) was stirred at 100 °Cfor 1 h. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLCQto afford the title compound (26.9 mg, 15.8%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 7.91 (d, J = 8.0 Hz, 1H), 7.69 – 7.54 (m, 2H), 7.37 – 7.29 (m, 1H), 3.77 (br, 1H), 2.75 (s, 3H), 2.73 – 2.63 (m, 2H), 2.17 (s, 3H), 2.10 – 1.99 (m, 2H), 1.99 - 1.87 (m, 2H), 1.60 - 1.33 (m, 2H). LCMSI: m / z = 323 [M+H]+Route B Preparation 22 – 2-hydroxy-4-methylquinoline-3-carbonitrile To a solution of o-aminoacetophenone (5.00 g, 37.0 mmol) and cyanoacetic acid (4.70 g, 55.2 mmol) in THF (25 mL) were added HOBt (497 mg, 3.69 mmol), EDCI (12.7 g, 66.1 mmol) and DIEA (9.47 g, 74.0 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was re-crystallized from DMSO / water (200 mL, 1 / 1) to afford the title compound (3.27 g, 48.0%) as a white solid. LCMS m / z: 185 [M+H]+Preparation 23 – 2-chloro-4-methylquinoline-3-carbonitrile. To a solution of 2-hydroxy-4-methylquinoline-3-carbonitrile (1.50 g, 8.14 mmol) in dioxane (30 mL) was added POCl3 (12.5 g, 81.4 mmol) over 5 min at 0 °C. The resulting mixture was stirred at 100 °C overnight. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in DCM (30 mL) and quenched by the addition of sat. NaHCO3 (aq.) (30 mL) at 0 °C and extracted with DCM (3 × 30 mL). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. This resulted in the title compound (1.40 g, crude) as a brown solid. LCMS m / z = 203 [M+H]+. Preparation 24 – 2-(cyanoamino)-4-methylquinoline-3-carbonitrile. To a solution of 2-chloro-4-methylquinoline-3-carbonitrile (800 mg, 3.95 mmol) in DMSO (20 mL) was added cyanamide, monosodium salt (508 mg, 7.94 mmol). The reaction mixture was stirred at 80 °C overnight. The mixture was allowed to cool down to room temperature and diluted with water (50 mL). The resulting mixture was extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLCBto afford the title compound (390 mg, 47.4%) as a light-yellow solid. LCMS m / z = 209 [M+H]+.Preparation 25 – 5-methyl-N2-(1-methylpiperidin-4-yl)pyrimido[4,5-b]quinoline-2,4-diamine. To a solution of 2-(cyanoamino)-4-methylquinoline-3-carbonitrile (390 mg, 1.87 mmol) in dioxane (20 mL) was added 1-methylpiperidin-4-amine (937 mg, 8.23 mmol). The resulting mixture was stirred at 100 °C for 2 h. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by Prep- HPLCBto afford the title compound (212.3 mg, 35.2%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 7.92 (d, J = 8.3 Hz, 1H), 7.68 - 7.57 (m, 2H), 7.33 (t, J = 7.5 Hz, 1H), 3.78 (br, 1H), 2.75 (s, 3H), 2.69 (d, J = 10.1 Hz, 2H), 2.18 (s, 3H), 2.09 - 2.01 (m, 2H), 1.95 (d, J = 12.4 Hz, 2H), 1.46 (s, 2H). LCMSIm / z = 323 [M+H]+. Example 11: 6-methyl-N3-(1-methylpiperidin-4-yl)-8,9-dihydro-7H- cyclopenta[4,5]pyrido[2,3-d]pyrimidine-1,3-diaminePreparation 26 – Mixture of 1-methyl-3-oxo-4,5,6,7-tetrahydro-3H-cyclopenta[c]pyridine-4- carbonitrile and 4-methyl-2-oxo-3,5,6,7-tetrahydro-2H-cyclopenta[b]pyridine-3-carbonitrile. To a mixture of 2-acetylcyclopentan-1-one (2.00 g, 15.9 mmol) and 2-cyanoacetamide (1.33 g, 15.9 mmol) in ethanol (20.0 mL) was added piperidine (1.35 g, 15.9 mmol). The mixture was stirred at 80 °C for 6 h. The mixture was allowed to cool down to room temperature. The precipitated solids were collected by filtration and washed with ethanol (3 × 50 mL). The solid was dried under vacuum to afford the title compound (1.67 g, crude, mixture of regioisomers) as a white solid. LCMS m / z = 175 [M+H]+. Preparation 27 – 3-chloro-1-methyl-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitrile and 2- chloro-4-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carbonitrile To a solution of a mixture of 1-methyl-3-oxo-4,5,6,7-tetrahydro-3H-cyclopenta[c]pyridine-4- carbonitrile and 4-methyl-2-oxo-3,5,6,7-tetrahydro-2H-cyclopenta[b]pyridine-3-carbonitrile (800 mg, 4.59 mmol) in dioxane (15.0 mL) was added POCl3 (7.04 g, 45.9 mmol) dropwise at 0 °C. The resulting mixture was stirred at 100 °C for 6 h. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The resulting mixture was diluted with CH2Cl2 (20 mL) and quenched with sat. NaHCO3 (aq.) at 0 °C. The resulting mixture was extracted with CH2Cl2(3 × 80 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA(5:1) to afford a mixture of two isomers (770 mg, 87.0%) as a white solid. The mixture was separated by SFCAto afford 3-chloro-1-methyl-6,7-dihydro-5H-cyclopenta[c]pyridine-4- carbonitrile (390 mg, Rt= 3 min) as a white solid and 2-chloro-4-methyl-6,7-dihydro-5H- cyclopenta[b]pyridine-3-carbonitrile (250 mg, Rt= 4 min) as a white solid. LCMS m / z = 193 [M+H]+Preparation 28 – N-(4-cyano-1-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-3-yl)cyanamide To a solution of 3-chloro-1-methyl-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitrile (360 mg, 1.87 mmol) and cyanamide (86.4 mg, 2.06 mmol) in dioxane (8.0 mL) were added BrettPhos Pd G3 (169 mg, 0.187 mmol), BrettPhos (100 mg, 0.187 mmol) and Cs2CO3(1.21g, 3.74 mmol). The mixture was stirred under nitrogen atmosphere at 100 °C for 1 h. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered through a short pad of Celite. The pad was washed with CH2Cl2(3 × 50 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLCBto afford the title compound (150 mg, 40.5%) as a white solid. LCMS m / z = 199 [M+H]+. Preparation 29 – 6-methyl-N3-(1-methylpiperidin-4-yl)-8,9-dihydro-7H- cyclopenta[4,5]pyrido[2,3-d]pyrimidine-1,3-diamine A solution of N-(4-cyano-1-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-3-yl)cyanamide (60 mg, 0.303 mmol) and 1-methylpiperidin-4-amine (41.5 mg, 0.364 mmol) in EtOH (1.5 mL) was stirred for 3 h at 80 °C. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by Prep-HPLCBto afford the title compound as a white solid.1H NMR (400 MHz, DMSO-d6) δ 6.56 (s, 2H), 6.27 (s, 1H), 3.86 – 3.62 (m, 1H), 2.85 – 2.70 (m, 4H), 2.37 (s, 3H), 2.16 (s, 3H), 2.13 – 2.03 (m, 2H), 1.94 (t, J = 11.5 Hz, 2H), 1.87 – 1.73 (m, 2H), 1.57 – 1.44 (m, 2H). LCMSAm / z = 313 [M+H]+Example 12: 5-methyl-N2-(1-methylpiperidin-4-yl)-7,8-dihydro-6H- cyclopenta[5,6]pyrido[2,3-d]pyrimidine-2,4-diaminePreparation 30 – N-(3-cyano-4-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)cyanamide To the solution of 2-chloro-4-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carbonitrile (230 mg, 1.194 mmol, synthesised as described in Example 11, Preparation 27) and cyanamide (55.2 mg, 1.31 mmol) in dioxane (5.0 mL) were added BrettPhos Pd G3 (108 mg, 0.119 mmol), BrettPhos (64.1 mg, 0.119 mmol) and Cs2CO3 (778 mg, 2.39 mmol). The mixture was stirredat 100 °C under nitrogen atmosphere for 1 h. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered through a short pad of Celite. The pad was washed with CH2Cl2(2 × 10 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLCBto afford the title compound (120 mg, 50.7%) as a yellow solid. LCMS m / z = 199 [M+H]+. Preparation 31 – 5-methyl-N2-(1-methylpiperidin-4-yl)-7,8-dihydro-6H- cyclopenta[5,6]pyrido[2,3-d]pyrimidine-2,4-diamine A mixture of N-(3-cyano-4-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)cyanamide (60.0 mg, 0.303 mmol) and 1-methylpiperidin-4-amine (51.9 mg, 0.455 mmol) in EtOH (1.5 mL) was stirred for 5 h at 80 °C. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered through a short pad of Celite. The pad was washed with CH2Cl2(3 × 10 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLCBto afford the title compound (31.3 mg, 33.1%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 6.63 (s, 2H), 6.26 (s, 1H), 3.82 – 3.67 (m, 1H), 2.88-2.86 (m, 4H), 2.75-2.71 (m, 2H), 2.57 (s, 3H), 2.16 (s, 3H), 2.07 – 1.99 (m, 2H), 1.98 – 1.87 (m, 2H), 1.86 - 1.81 (m, 2H), 1.57 – 1.42 (m, 2H). LCMSOm / z = 313 [M+H]+Example 13: 7-methyl-N2-(1-methylpiperidin-4-yl)-5-phenylpyrido[2,3-d] pyrimidine-2,4- diaminePreparation 32 – 2-hydroxy-6-methyl-4-phenylpyridine-3-carbonitrile To a solution of 4-phenylbut-3-en-2-one (2.00 g, 13.7 mmol) and cyanoacetamide (1.38 g, 16.4 mmol) in DMSO (2.00 mL) was added t-BuOK (6.14 g, 54.7 mmol). The resulting mixture was stirred at 60 °C overnight. The resulting mixture was filtered through a short pad of Celite. The pad was washed with EtOAc (10 mL). The combined filtrate was diluted with water (10 mL) and extracted with EtOAc (10 mL×3). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduce pressure. The residue was purified by Prep-HPLCAto afford the title compound as a white solid (210 mg, 7.3%). LCMS m / z = 211 [M+H]+. Preparation 33 – 2-chloro-6-methyl-4-phenylpyridine-3-carbonitrileThe solution of 2-hydroxy-6-methyl-4-phenylpyridine-3-carbonitrile (200 mg, 0.952 mmol) in POCl3(3.0 mL) was stirred at 100 °C overnight. The resulting mixture was concentrated under reduce pressure. The residue was purified by Prep-HPLCSto afford the title compound as a yellow solid (120 mg, 55.2%). LCMS m / z = 229 [M+H]+. Preparation 34 – 2-(cyanoamino)-6-methyl-4-phenylpyridine-3-carbonitrile To a solution of 2-chloro-6-methyl-4-phenylpyridine-3-carbonitrile (110 mg, 0.481 mmol) in DMSO (3.0 mL) at room temperature was added cyanamide, monosodium salt (61.6 mg, 0.962 mmol, 2.00 equiv). The resulting mixture was stirred 100 °C overnight. The reaction mixture was allowed to cool to room temperature and quenched by the addition of water (10 mL). The mixture was extracted with EtOAc (10 mL×3). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduce pressure. The residue was further purified by Prep-HPLCSto afford the title compound as a white solid (60.0 mg, 53.2%). LCMS m / z = 235 [M+H]+. Preparation 35 – 7-methyl-N2-(1-methylpiperidin-4-yl)-5-phenylpyrido[2,3-d] pyrimidine-2,4- diamine To a solution of 2-(cyanoamino)-6-methyl-4-phenylpyridine-3-carbonitrile (50.0 mg, 0.213 mmol) in dioxane (1.5 mL) at room temperature was added 1-methylpiperidin-4-amine (29.2 mg, 0.260 mmol). The resulting mixture was stirred at 80 °C overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLCTto afford the title compound as a white solid (18.5 mg, 24.6%).1H NMR (400 MHz, DMSO-d6) δ 7.63 – 7.49 (m, 3H), 7.47 – 7.37 (m, 2H), 6.67 (s, 1H), 6.58 (s, 1H), 3.90 – 3.73 (m, 1H), 2.76 - 2.73 (m, 2H), 2.46 (s, 3H), 2.16 (s, 3H), 1.95 – 1.92 (m, 2H), 1.83 - 1.80 (m, 2H), 1.59 – 1.43 (m, 2H). LCMS m / z = 349 [M+H]+. Example 14: (R)-5,7-dimethyl-N2-(1-methylpyrrolidin-3-yl)pyrido[2,3-d]pyrimidine-2,4- diamineTo a stirred solution of 2-(cyanoamino)-4,6-dimethylpyridine-3-carbonitrile (100 mg, 0.581 mmol, and (3R)-1-methylpyrrolidin-3-amine dihydrochloride (121 mg, 0.697 mmol) in EtOH (4.0 mL) was added DIEA (150 mg, 1.16 mmol) at room temperature. The resulting mixture was stirred at 80 °C overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLCANto afford the title compound (62.4 mg,39.5%) as a white solid.1H NMR (400 MHz, Methanol-d4) δ 6.81 (s, 1H), 4.67- 4.57 (m, 1H), 2.98 (t, J = 8.8 Hz, 1H), 2.92 – 2.75 (m, 1H), 2.72 (s, 3H), 2.66 – 2.54 (m, 2H), 2.47 (s, 3H), 2.45 – 2.31 (m, 4H), 1.85 – 1.74 (m, 1H). LCMSHm / z = 273 [M+H]+Example 15: (S)-5,7-dimethyl-N2-(1-methylpyrrolidin-3-yl)pyrido[2,3-d]pyrimidine-2,4- diamineAs described for Example 14 using (3S)-1-methylpyrrolidin-3-amine dihydrochloride and purification by Prep-HPLCUto afford the title compound (41.6 mg, 26.3%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 6.95 - 6.46 (m, 4H), 4.48 - 4.35 (m, 1H), 2.88 - 2.72 (m, 1H), 2.64 (s, 3H), 2.58 - 2.54 (m, 1H), 2.47 - 2.41 (m, 1H), 2.41 - 2.31 (m, 4H), 2.26 (s, 3H), 2.20 - 2.08 (m, 1H), 1.78 - 1.63 (m, 1H). LCMSHm / z = 273 [M+H]+. Example 16: 5-methyl-N2-(1-methylpiperidin-4-yl)-7-phenylpyrido[2,3-d]pyrimidine-2,4- diaminePreparation 36 – 2-chloro-4-methyl-6-phenylpyridine-3-carbonitrile To a solution of 2,6-dichloro-4-methylpyridine-3-carbonitrile (1.00 g, 5.37 mmol) and phenyl boronic acid (521 mg, 4.27 mmol) in DME (5.0 mL) and H2O (1.0 mL) were added Pd(PPh3)4 (617 mg, 0.530 mmol) and Na2CO3 (1.13 g, 10.6 mmol). The mixture was irradiated with microwave radiation under nitrogen atmosphere at 80 °C for 1 h. The mixture was allowed to cool down to room temperature and quenched by the addition of water (50 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLCLto afford the title compound (420 mg, 34.3%) as a white solid. LCMS m / z = 229 [M+H]+Preparation 37 – 2-(cyanoamino)-4-methyl-6-phenylpyridine-3-carbonitrile To a mixture of 2-chloro-4-methyl-6-phenylpyridine-3-carbonitrile (410 mg, 1.79 mmol) and aminoformonitrile (150 mg, 3.58 mmol) in dioxane (5.0 mL) were added Brettphos Pd G3 (162 mg, 0.170 mmol), Brettphos (96.2 mg, 0.170 mmol) and Cs2CO3 (1.16 g, 3.58 mmol). Themixture was stirred under nitrogen atmosphere at 100 °C for 2 h. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered through a short pad of Celite. The pad was washed with DCM (30 mL). The combined filtrated was concentrated under reduced pressure. The residue was purified by Prep-HPLCLto afford the title compound (302 mg, 71.9%) as a yellow solid. LCMS m / z = 235 [M+H]+. Preparation 38 – 5-methyl-N2-(1-methylpiperidin-4-yl)-7-phenylpyrido[2,3-d]pyrimidine-2,4- diamine A solution of 2-(cyanoamino)-4-methyl-6-phenylpyridine-3-carbonitrile (190 mg, 0.811 mmol) and 1-methylpiperidin-4-amine (648 mg, 5.67 mmol) in DMSO (2.0 mL) was irradiated with microwave radiation at 180 °C for 2 h. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered through a short pad of Celite. The pad was washed with EtOAc (10 mL). The combined filtrate was concentrated under reduce pressure. The residue was purified by Prep-HPLCWto afford the title compound (26.6 mg, 9.41%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.19 – 8.08 (m, 2H), 7.55 – 7.45 (m, 3H), 7.42 (s,1H), 6.76 (br, 2H),6.44 (br, 1H), 3.93 – 3.78 (m, 1H), 2.82 – 2.70 (m, 5H), 2.17 (s, 3H), 1.98 (t, J = 12.0 Hz, 2H), 1.82 (d, J = 12.0 Hz, 2H), 1.60 – 1.45 (m, 2H). LCMSCm / z = 349 [M+H]+Example 17: 7-methoxy-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diaminePreparation 39 – 2-(cyanoamino)-6-methoxypyridine-3-carbonitrile To a mixture of 2-bromo-6-methoxypyridine-3-carbonitrile (300 mg, 1.41 mmol) in dioxane (3.00 mL) was added cyanamide (118 mg, 2.82 mmol), Brettphos Pd G3 (1.28 g, 1.41 mmol), Brettphos (756 mg, 1.41 mmol) and K2CO3 (389 mg, 2.82 mmol) at room temperature. The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered through a short pad of Celite. The pad was washed with EtOAc (5 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLCBto afford the title compound as white solid (130 mg, 53.0%). LCMS m / z = 175 [M+H]+Preparation 40 – 7-methoxy-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamine To a solution of 2-(cyanoamino)-6-methoxypyridine-3-carbonitrile (130 mg, 0.746 mmol) in dioxane (1.30 mL) was added 1-methylpiperidin-4-amine (102 mg, 0.895 mmol) atroom temperature. The resulting mixture was stirred at 80 °C for 6 h. The mixture was allowed to cool down to room temperature. The crude product was purified by Prep-HPLCIto afford the title compound (95.6 mg, 44.4%).1H NMR (400 MHz, DMSO-d6) δ 8.21 (d, J = 8.6 Hz, 1H), 7.41 – 6.99 (br, 2H), 6.43 (d, J = 8.6 Hz, 2H), 3.87 (br, 4H), 2.73 (d, J = 10.5 Hz, 2H), 2.16 (s, 3H), 1.96 (t, J = 11.6 Hz, 2H), 1.86 – 1.75 (m, 2H), 1.51 (m, 2H). LCMSHm / z = 289 [M+H]+Example 18: N2-(1-methylpiperidin-4-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4- diaminePreparation 41 – 2-(cyanoamino)-6-(trifluoromethyl)pyridine-3-carbonitrile To a mixture of 2-chloro-6-(trifluoromethyl)pyridine-3-carbonitrile (1.00 g, 4.84 mmol) in DMSO (10.0 mL) was added cyanamide, monosodium salt (619 mg, 9.68 mmol). The mixture was stirred for 2 h at 100 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLCBto afford the title compound as a light brown solid (618 mg, 60.1%). LCMS m / z = 211 [M-H]- Preparation 42 – N2-(1-methylpiperidin-4-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4- diamine To a mixture of 2-(cyanoamino)-6-(trifluoromethyl)pyridine-3-carbonitrile (200 mg, 0.943 mmol, 1.00 equiv) in dioxane (5.00 mL) was added 1-methylpiperidin-4-amine (215 mg, 1.88 mmol, 2.00 equiv). The mixture was stirred for 2 h at 100 °C. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLCWto afford the title compound as a white solid (182.9 mg, 59.5%).1H NMR (400 MHz, Methanol- d4) δ 8.49 (d, J = 8.1 Hz, 1H), 7.39 (d, J = 8.1 Hz, 1H), 4.84 (s, 1H), 3.98 (dt, J = 11.2, 6.7 Hz, 1H), 2.87 (d, J = 11.7 Hz, 2H), 2.45 – 2.13 (m, 5H), 2.05 (d, J = 13.7 Hz, 2H), 1.60-1.59 (m, 2H). LCMSHm / z = 327 [M+H]+Example 19: N2-(1-methylpiperidin-4-yl)-6-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4- diaminePreparation 43 – 2-(cyanoamino)-5-(trifluoromethyl)pyridine-3-carbonitrileA mixture of 2-chloro-5-(trifluoromethyl)pyridine-3-carbonitrile (500 mg, 2.42 mmol) and cyanamide, monosodium salt (309 mg, 4.84 mmol) in DMSO (5.0 mL) was stirred at 100 °C for 1 h. The mixture was allowed to cool down to room temperature and acidified to pH 1 with aq. HCl (6.0 M). The precipitated solids were collected by filtration and dried under vacuum to afford the title compound (200 mg crude) as a grey solid. LCMS m / z = 213 [M+H]+Preparation 44 – N2-(1-methylpiperidin-4-yl)-6-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4- diamine A mixture of 2-(cyanoamino)-5-(trifluoromethyl)pyridine-3-carbonitrile (195 mg, 0.919 mmol) and 1-methylpiperidin-4-amine (209 mg, 1.83 mmol) in dioxane (3.0 mL) was stirred at 100 °C for 1 h. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The crude product was purified by Prep-HPLCYto afford the title compound (142 mg, 47.3%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.06 – 8.65 (m, 2H), 8.36 – 7.45 (m, 2H), 7.45 – 7.00 (m, 1H), 3.87 (s, 1H), 2.94 – 2.70 (m, 2H), 2.37 (m, 3H), 2.17 – 1.96 (m, 2H), 1.93 – 1.75 (m, 2H), 1.66 – 1.47 (m, 2H). LCMSCm / z = 327 [M+H]+Example 20: 6-bromo-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamineRoute A Preparation 45 – N-(5-bromo-3-cyanopyridin-2-yl)cyanamide To a solution of 5-bromo-2-chloronicotinonitrile (1.00 g, 4.60 mmol) in DMSO (10.0 mL) at room temperature was added cyanamide, monosodium salt (0.290 g, 4.60 mmol). The resulting mixture was stirred at 80 °C for 1 h. The reaction was quenched with water at room temperature. The resulting mixture was filtered. The filter cake was purified by Prep-HPLCPto afford the title compound (450 mg, 43.9%). LCMS m / z = 225 [M+H]+Preparation 46 – 6-bromo-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamine To a solution of N-(5-bromo-3-cyanopyridin-2-yl)cyanamide (300 mg, 1.34 mmol) in dioxane (5.0 mL) at room temperature was added 1-methylpiperidin-4-amine (307 mg, 2.69 mmol). The resulting mixture was stirred at 100 °C for 1.5 h. The resulting mixture was concentrated under vacuum. The residue was purified by Prep-HPLCAAto afford the title compound as a white solid (340 mg, 74.1%).1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 2H), 7.81 - 7.35 (m, 2H), 7.11 - 6.51 (m, 1H), 3.87 - 3.71 (m, 1H), 2.74 (d, J = 8.0 Hz, 2H), 2.15 (s,3H), 1.93 (t, J = 12.0 Hz, 2H), 1.84 - 1.74 (m, 2H), 1.58 - 1.45 (m, 2H). LCMSLm / z = 339 [M+H]+. Route B Preparation 47 – 6-bromo-2-chloropyrido[2,3-d]pyrimidin-4-amine A solution of 6-bromo-2,4-dichloropyrido[2,3-d]pyrimidine (200 mg, 0.717 mmol) and NH3.H2O (3.0 mL) was stirred was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum to afford the title compound (200 mg, crude) as a yellow solid. LCMS m / z = 261 [M+H]+Preparation 48 – 6-bromo-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamine To a solution of 6-bromo-2-chloropyrido[2,3-d]pyrimidin-4-amine (90.0 mg, 0.347 mmol) and 1-methylpiperidin-4-amine (396 mg, 3.47 mmol) in DMSO (1.0 mL) was added Cs2CO3(339 mg, 1.04 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 3 h. The resulting mixture was purified by Prep-HPLCAKto afford the title compound (14.1 mg, 12.1%) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 2H), 7.87 -7.34 (m, 2H), 7.06 – 6.79 (m, 1H), 3.86 - 3.72 (m, 1H), 2.74 (dd, J = 11.2, 4.3 Hz, 2H), 2.15 (s, 3H), 2.01 - 1.87 (m, 2H), 1.85 - 1.73 (m, 2H), 1.59 - 1.44 (m, 2H). LCMSHm / z = 339 [M+H]+Example 21: 6-bromo-7-methyl-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4- diaminePreparation 49 – 5-bromo-2-(cyanoamino)-6-methylpyridine-3-carbonitrile To a mixture of 5-bromo-2-chloro-6-methylpyridine-3-carbonitrile (500 mg, 2.16 mmol) in DMSO (5.00 mL) was added cyanamide, monosodium salt (207 mg, 3.24 mmol). The mixture was stirred at 80 °C overnight. The resulting mixture was purified by Prep-HPLCACto afford the title compound (168 mg, crude) as a brown solid. LCMS m / z = 239 [M+H]+Preparation 50 – 6-bromo-7-methyl-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4- diamine To a mixture of 5-bromo-2-(cyanoamino)-6-methylpyridine-3-carbonitrile (158 mg, 0.533 mmol) in dioxane (2.50 mL) was added 1-methylpiperidin-4-amine (121 mg, 1.06 mmol). The mixture was stirred at 100 °C for 2 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLCADto afford the title compound as awhite solid (21.7 mg, 11.5%).1H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 7.78 – 7.14 (br, 2H), 6.68 (s, 1H), 3.84 – 3.72 (m, 1H), 2.74 (d, J = 11.5 Hz, 2H), 2.56 (s, 3H), 2.16 (s, 3H), 1.94 (t, J = 11.5 Hz, 2H), 1.80 (d, J = 12.3 Hz, 2H), 1.58 – 1.44 (m, 2H). LCMSCm / z = 353 [M+H]+Example 22: 6-bromo-5,7-dimethyl-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine- 2,4-diaminePreparation 51 – N-(5-bromo-3-cyano-4,6-dimethylpyridin-2-yl)cyanamide To a solution of 5-bromo-2-chloro-4,6-dimethylnicotinonitrile (2.00 g, 8.14 mmol) and cyanamide, monosodium salt (1.04 g, 16.2 mmol) in DMSO (20.0 mL) was stirred at 80 °C for 2 h. The mixture was allowed to cool down to room temperature and acidified to pH 6 with aq. HCl (1 M). The solid was collected by filtration. The solid was purified by trituration with PE / EA (2:1, 30 mL) to afford the title compound as a light brown solid (1.3 g, 63.6%). LCMS m / z = 253 [M+H]+Preparation 52 – 6-bromo-5,7-dimethyl-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine- 2,4-diamine To a solution of N-(5-bromo-3-cyano-4,6-dimethylpyridin-2-yl)cyanamide (100 mg, 0.398 mmol) and 1-methylpiperidin-4-amine (90.8 mg, 0.796 mmol) in dioxane (2.00 mL) was stirred at 100°C overnight. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLCAEto afford the title compound as a white solid (21.9 mg, 15.0%).1H NMR (400 MHz, DMSO-d6) δ 7.00 - 6.88 (br, 2H), 6.73 - 6.70 (br, 1H), 3.81-3.71 (m, 1H), 2.76-2.73 (m, 5H), 2.50 (s, 3H), 2.16 (s, 3H), 1.97 - 1.92 (m, 2H), 1.80 - 1.77(m, 2H), 1.56 - 1.46 (m, 2H). LCMSCm / z = 267 [M+H]+Example 23: 7-chloro-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamineRoute A Preparation 53 – 2,7-dichloropyrido[2,3-d]pyrimidin-4-amineA solution of 2,4,7-trichloropyrido[2,3-d]pyrimidine (200 mg, 0.853 mmol) in NH3.H2O (3.0 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford the title compound as white solid (190 mg, crude). LCMS m / z = 217 [M+H]+Preparation 54 – 7-chloro-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamine To a stirred solution of 2,7-dichloropyrido[2,3-d]pyrimidin-4-amine (150 mg, 0.698 mmol) and 1-methylpiperidin-4-amine (398 mg, 3.49 mmol) in DMSO (3.00 mL) was added DIEA (180 mg, 1.40 mmol) at room temperature. The resulting mixture was stirred at 60 °C for 1 h. The mixture was allowed to cool down to room temperature. The crude product was purified by Prep-HPLCUto afford 7-chloro-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamine as an off-white solid (6.9 mg, 3.34%).1H NMR (400 MHz, DMSO-d6) δ 8.40 – 8.30 (m, 1H), 8.00 – 7.37 (m, 2H), 7.16 – 6.82 (m, 2H), 3.85 – 3.72 (m, 1H), 2.80 – 2.68 (m, 2H), 2.16 (s, 3H), 2.00 – 1.86 (m, 2H), 1.84 – 1.73 (m, 2H), 1.58 – 1.38 (m, 2H). LCMSHm / z = 293 [M+H]+. Route B Preparation 55 – 6-chloro-2-(cyanoamino)pyridine-3-carbonitrile To a solution of 2,6-dichloropyridine-3-carbonitrile (30.0 g, 173 mmol) in DMSO (240 mL) at room temperature was added cyanamide, monosodium salt (22.2 g, 347 mmol). The resulting mixture was stirred at 60 °C for 1 h. The mixture was allowed to cool down to room temperature. The residue was purified by Prep-HPLCBto afford the title compound as a red solid (10.0 g, 32.3%). LCMS m / z = 179 [M+H]+Preparation 56 – 7-chloro-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamine To a stirred solution of 6-chloro-2-(cyanoamino)pyridine-3-carbonitrile (10.0 g, 56.0 mmol) in dioxane (150 mL) was added 1-methylpiperidin-4-amine (7.67 g, 67.2 mmol) at room temperature. The resulting mixture was stirred at 100oC for 1 h. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was dissolved in DMF (10.0 mL). The residue was purified by Prep- HPLCBto afford the title compound as a yellow solid (3.00 g, 18.3%).1H NMR (400 MHz, DMSO-d6) δ 8.40 – 8.30 (m, 1H), 8.00 – 7.37 (m, 2H), 7.16 – 6.82 (m, 2H), 3.85 – 3.72 (m, 1H), 2.80 – 2.68 (m, 2H), 2.16 (s, 3H), 2.00 – 1.86 (m, 2H), 1.84 – 1.73 (m, 2H), 1.58 – 1.38 (m, 2H). Example 24: 7-(4-methoxyphenyl)-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine- 2,4-diamineNH2MPreparation 57 – N-(3-cyano-6-(4-methoxyphenyl)pyridin-2-yl)cyanamide To a solution of 6-chloro-2-(cyanoamino)pyridine-3-carbonitrile (150 mg, 0.840 mmol, synthesised as described in Example 23, Preparation 55) and (4-methoxyphenyl)boronic acid (255 mg, 1.68 mmol) in 1,4-dioxane (3.0 mL) and H2O (0.6 mL) were added Pd(AMPHOS)2Cl2(59.5 mg, 0.084 mmol) and K3PO4(356 mg, 1.68 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred under nitrogen atmosphere at 100 °C for 3 h. The resulting mixture was purified by Prep- HPLCBto afford the title compound as a yellow solid (80.0 mg, 38.1%). LCMS m / z = 251 [M+H]+Preparation 58 – 7-(4-methoxyphenyl)-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4- diamine To a stirred solution of N-(3-cyano-6-(4-methoxyphenyl) pyridin-2-yl)cyanamide (80.0 mg, 0.320 mmol) in 1,4-dioxane (1.0 mL) at room temperature was added 1-methylpiperidin-4- amine (73.0 mg, 0.640 mmol). The resulting mixture was stirred at 80 °C for 4 h. The resulting mixture was concentrated under vacuum. The residue was purified by Prep-HPLCIto afford the title compound as a white solid (17.0 mg, 14.2%).1H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J = 8.3 Hz, 1H), 8.14 (d, J = 8.0 Hz, 2H), 7.56 (d, J = 8.0 Hz, 1H), 7.32 (s, 2H), 7.05 (d, J = 8.0 Hz, 2H), 6.52 (s, 1H), 3.94 - 3.76 (m, 4H), 2.75 (d, J = 11.2 Hz, 2H), 2.17 (s, 3H), 1.98 (t, J = 11.5 Hz, 2H), 1.83 (d, J = 12.2 Hz, 2H), 1.60 - 1.45 (m, 2H); LCMSMm / z: 365 [M+H]+. Example 25: N2-(1-methylpiperidin-4-yl)-7-(pyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4- diamineTo a stirred solution of 7-chloro-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4- diamine (60.0 mg, 0.205 mmol) and pyridin-3-ylboronic acid (50.4 mg, 0.410 mmol) in dioxane (1.5 mL) / H2O (0.5 mL) were added Pd(AMPhos)2Cl2(14.5 mg, 21.0 μmol) and K3PO4(87.0 mg, 0.410 mmol) at room temperature. The resulting mixture was stirred under nitrogen atmosphere at room temperature for 1 h. The mixture was allowed to cool down to roomtemperature. The residue was purified by Prep-HPLCAFto afford the title compound (29.4 mg, 42.8%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 9.32 (d, J = 2.3 Hz, 1H), 8.67 (dd, J = 4.8, 1.6 Hz, 1H), 8.56 – 8.44 (m, 2H), 7.70 (d, J = 8.2 Hz, 1H), 7.54 (dd, J = 8.0, 4.7 Hz, 1H), 7.46 (br, 2H), 6.92 – 6.59 (m, 1H), 3.87 (br, 1H), 2.76 (d, J = 11.3 Hz, 2H), 2.17 (s, 3H), 1.96 (d, J = 11.7 Hz, 2H), 1.83 (d, J = 12.3 Hz, 2H), 1.62 – 1.47 (m, 2H). LCMSCm / z = 336 [M+H]+Example 26: 7-(1-methyl-1H-pyrazol-4-yl)-N2-(1-methylpiperidin-4-yl)pyrido[2,3- d]pyrimidine-2,4-diamineAs described for Example 25, using 1-methyl-4-(3,3,4,4-tetramethylborolan-1-yl)-1H-pyrazole and purification by Prep-HPLCNto afford the title compound (14.4 mg, 24.9%) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 8.29 (d, J = 8.3 Hz, 1H), 8.06 (s, 1H), 7.57 – 7.04 (m, 3H), 6.53 (br, 1H), 3.90 (s, 3H), 3.83 -3.81 (m, 1H), 2.76 - 2.73 (m, 2H), 2.17 (s, 3H), 1.96 (t, J = 11.4 Hz, 2H), 1.81 (d, J = 12.2 Hz, 2H), 1.61 – 1.44 (m, 2H). LCMSCm / z = 339 [M+H]+Example 27: N2-(1-methylpiperidin-4-yl)-7-phenylpyrido[2,3-d]pyrimidine-2,4-diamineRoute A As described for Example 25, using phenyl boronic acid and purification by Prep-HPLCAHto afford the title compound as a white solid (22.3 mg, 39.0%).1H NMR (300 MHz, DMSO-d6) δ 8.43 (d, J = 9.0 Hz, 1H), 8.20 – 8.13 (m, 2H), 7.62 (d, J = 9.0 Hz, 1H), 7.56 – 7.35 (m, 5H), 6.70 – 6.45 (s, 1H), 3.82 (br, 1H), 2.76 (d, J = 12.0 Hz, 2H), 2.17 (s, 3H), 1.98 (t, J = 12.0 Hz, 2H), 1.83 (d, J = 12.0 Hz, 2H), 1.65 – 1.45 (m, 2H). LCMSCm / z = 335 [M+H]+. Route B Preparation 59 – 7-chloro-1H,3H-pyrido[2,3-d]pyrimidine-2,4-dione To a solution of 2-amino-6-chloropyridine-3-carboxamide (4.00 g, 23.3 mmol) in toluene (40.0 mL) at room temperature was added (COCl)2(3.55 g, 28.0 mmol). The resulting mixture wasstirred at 100 °C for 2 h. The mixture was allowed to cool down to room temperature. The precipitated solids were collected by filtration and washed with toluene (3 × 5 mL). The resulting solid was dried under vacuum to afford the title compound (4.00 g, crude) as a brown solid. LCMS m / z = 198 [M+H]+. Preparation 60 – 7-phenyl-1H,3H-pyrido[2,3-d]pyrimidine-2,4-dione To a stirred solution of 7-chloro-1H,3H-pyrido[2,3-d]pyrimidine-2,4-dione (3.00 g, 15.2 mmol) and phenyl boronic acid (2.22 g, 18.2 mmol) in 1,4-dioxane (60.0 mL) and H2O (20.0 mL) at room temperature were added Pd(AMPHOS)2Cl2(1.08 g, 1.52 mmol) and K3PO4(6.45 g, 30.4 mmol). The resulting mixture was stirred under nitrogen atmosphere at 100 °C for 2 h. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with H2O (100 mL) and extracted with CH2Cl2(3 × 200 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the combined filtrate was concentrated under reduced pressure. The residue was purified by trituration with Et2O (200 mL) to afford the title compound (3.50 g, crude) as a brown solid. LCMS m / z = 240 [M+H]+. Preparation 61 – 2,4-dichloro-7-phenylpyrido[2,3-d]pyrimidine A mixture of 7-phenylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (2.80 g, 11.7 mmol) in phosphorus oxychloride (100 mL) was stirred at 110 °C overnight. The resulting mixture was concentrated under reduced pressure. The residue was quenched by the addition of sat. NaHCO3 (aq.) (100 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 × 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2:1) to afford the title compound (640 mg, 19.9%) as a green solid. LCMS m / z = 278 [M+H]+Preparation 62 – 2-chloro-7-phenylpyrido[2,3-d]pyrimidin-4-amine A solution of 2,4-dichloro-7-phenylpyrido[2,3-d]pyrimidine (200 mg, 0.724 mmol) in NH3.H2O (3.0 mL) was stirred was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum to afford the title compound (230 mg, crude) as a white solid. LCMS m / z = 257 [M+H]+Preparation 63 – N2-(1-methylpiperidin-4-yl)-7-phenylpyrido[2,3-d]pyrimidine-2,4-diamine A solution of 2-chloro-7-phenylpyrido[2,3-d]pyrimidin-4-amine (190 mg, 0.740 mmol) in dioxane (3.0 mL) at room temperature was added 1-methylpiperidin-4-amine (169 mg, 1.48 mmol). The resulting mixture was stirred at 100 °C for 10 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLCALto afford the title compound (10.1 mg, 4.03%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J= 8.3 Hz, 1H), 8.21 - 8.12 (m, 2H), 7.62 (d, J = 8.3 Hz, 1H), 7.56 - 7.44 (m, 5H), 6.88 - 6.49 (m 82 (m E ,4- diTo a solution of 6-bromo-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamine (200 mg, 0.593 mmol) and oxetan-3-ol (87.9 mg, 1.19 mmol) in toluene (4.0 mL) were added Rockphos (41.7 mg, 89.0 μmol), Cs2CO3 (290 mg, 0.889 mmol) and bis(chloro(prop-2-en-1- yl)palladium) (10.9 mg, 30.0 μmol) at room temperature. The resulting mixture was stirred under nitrogen atmosphere at 90 °C for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLCAKto afford the title compound (2.8 mg, 1.43%) as a yellow solid.1H NMR (400 MHz, Methanol-d4) δ 8.48 (s, 1H), 7.66 (s, 1H), 5.35-5.34 (m, 1H), 5.09-5.06 (m, 2H), 4.88-4.71 (m, 2H), 4.18 (s, 1H), 3.49-3.46 (m, 2H), 3.25- 3.12 (m, 2H), 2.80 (s, 3H), 2.22 -2.20 (m, 2H), 1.97-1.86 (m, 2H). LCMSHm / z = 331 [M+H]+Example 29: N2-(3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)propyl)-5,7-dimethylpyrido[2,3- d]pyrimidine-2,4-diaminePreparation 64 – N2-(3,3-diethoxypropyl)-5,7-dimethylpyrido[2,3-d]pyrimidine-2,4-diamine Route A To a mixture of 2-(cyanoamino)-4,6-dimethylpyridine-3-carbonitrile (5.00 g, 29.0 mmol) in dioxane (50.0 mL) was added 3,3-diethoxypropan-1-amine (9.40 mL, 58.0 mmol). The mixture was stirred at 100 °C for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with EA / PE (30.0 mL / 60 mL). The solid was collected by filtration and washed with EA / PE (1:2, 3×10 mL). This resulted in the title compound as a brown solid (4.48 g, crude). LCMS m / z = 320 [M+H]+Route BTo a stirred mixture of 2-chloro-5,7-dimethylpyrido[2,3-d]pyrimidin-4-amine (4.30 g, 20.6 mmol, synthesized as described in Example 5, Preparation 13) in 1,4-dioxane (86.0 mL) was added 3,3-diethoxypropan-1-amine (4.55 g, 30.9 mmol, 1.50 equiv) dropwise at room temperature. The resulting mixture was stirred at 100 °C for 5 h. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by Prep-HPLCBto afford the title compound (2.33 g, 35.4%) as a yellow solid. LCMS m / z = 320 [M+H]+Preparation 65 – 3-((4-amino-5,7-dimethylpyrido[2,3-d]pyrimidin-2-yl)amino)propanal To a mixture of N2-(3,3-diethoxypropyl)-5,7-dimethylpyrido[2,3-d]pyrimidine-2,4-diamine (1.00 g, 3.13 mmol) in DCM (10.0 mL) was added TFA (2.00 mL). The mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with EA / PE (10.0 mL / 5 mL). The crude product was collected by filtration and dried under vacuum to afford the title compound as a white solid (570 mg, crude). LCMS m / z = 246 [M+H]+Preparation 66 – N2-(3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)propyl)-5,7-dimethylpyrido[2,3- d]pyrimidine-2,4-diamine To a solution of 3-((4-amino-5,7-dimethylpyrido[2,3-d]pyrimidin-2-yl)amino)propanal (80.0 mg, 0.326 mmol) in MeOH (2.0 mL) was added Et3N (131 mg, 1.30 mmol) and 2-oxa-6- azaspiro[3.3]heptane hemioxalate (188 mg, 0.652 mmol). The solution was stirred at room temperature for 1 h and followed by the addition of NaBH4 (24.6 mg, 0.652 mmol). The resulting mixture was stirred at room temperature for additional 1 h and concentrated under reduced pressure. The crude product was purified by Prep-HPLCNto afford the title compound as a white solid (22.2 mg, 20.7%).1H NMR (400 MHz, DMSO-d6) δ 6.85 – 6.61 (m, 3H), 6.47(s, 1H), 4.58 (s, 4H), 3.28 – 3.21 (m, 2H), 3.21 (s, 4H), 2.63 (s, 3H), 2.37 (s, 3H), 2.33 (t, J = 7.0 Hz, 2H), 1.54 – 1.45 (m, 2H). LCMSHm / z = 329 [M+H]+Example 30: N2-(2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethyl)-5,7-dimethylpyrido[2,3- d]pyrimidine-2,4-diamineAs described for Example 29, using 2,2-diethoxyethan-1-amine and final purification by Prep- HPLCYto afford the title compound (28.4 mg, 26.1%) as a white solid.1H NMR (400 MHz,DMSO-d6) δ 6.74 (s, 2H), 6.69 (s, 1H), 6.30 (s, 1H), 4.58 (s, 4H), 3.25 - 3.16 (m, 4H), 3.19- 3.11 (m, 2H), 2.63 (s, 3H), 2.49 - 2.44 (m, 2H), 2.37 (s, 3H). LCMSHm / z = 315 [M+H]+Example 31: N3-(1-methylpiperidin-4-yl)-6-phenylpyrimido[4,5-c]isoquinoline-1,3- diaminePreparation 67 – 1-(3-chloro-1-phenylisoquinolin-4(3H)-ylidene)-N,N-dimethylmethanamine A solution of POCl3(6.72 g, 43.8 mmol) in THF (15 mL) was treated with DMF (3.20 g, 43.7 mmol) for 30 min at 0 °C followed by the addition of 1-phenyl-1,4-dihydroisoquinolin-3(2H)- one (2.47 g, 10.9 mmol). The resulting mixture was stirred for 3 h at room temperature. The reaction was quenched by the addition of NaOH (2 mol / L, 20 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 50mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. This resulted in the title compound as a brown oil (5.3 g, crude). LCMS m / z = 297 [M+H]+Preparation 68 – 3-chloro-1-phenylisoquinoline-4-carbaldehyde A solution of 1-(3-chloro-1-phenylisoquinolin-4(3H)-ylidene)-N,N-dimethylmethanamine (5.2 g, 17.5 mmol) and KMnO4 (1.50 mg) in H2SO4 (50 mL) was stirred for 1 h at room temperature. The mixture was allowed to cool down to room temperature. The reaction was quenched with water at room temperature. The precipitated solids were collected by filtration and washed with water (3 x 10 mL). The residue was purified by trituration with EtOAc (20 mL). The resulting mixture was filtered, the filter cake was washed with EtOAc (3 x 10 mL). The filtrate was concentrated under reduced pressure. This resulted in the title compound (1.5 g, crude) as a brown solid. LCMS m / z = 268 [M+H]+Preparation 69 – N-[(3-chloro-1-phenylisoquinolin-4-yl)methylidene]hydroxylamine A solution of 3-chloro-1-phenylisoquinoline-4-carbaldehyde (1.14 g, 4.26 mmol), Et3N (764 uL, 5.50 mmol) and hydroxylamine hydrochloride (433 mg, 6.23 mmol) in EtOH (5 mL) was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (5 mL). The resulting mixture was extracted with EtOAc (3 x 10mL). The combined organic layers were washed with brine (3 x 5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLCBto afford the title compound as an orange solid (476 mg, 39.5%). LCMS m / z = 283 [M+H]+Preparation 70 – 3-chloro-1-phenylisoquinoline-4-carbonitrile To a stirred solution of N-[(3-chloro-1-phenylisoquinolin-4-yl)methylidene]hydroxylamine (426 mg, 1.51 mmol) in DCM (5.0 mL) was added pyridine (244 uL, 3.01 mmol,) dropwise at room temperature. The resulting mixture was stirred for 5 min at 0 °C. To the above mixture was added TFAA (838 uL, 6.03 mmol) dropwise at room temperature. The resulting mixture was stirred for additional overnight at room temperature. The resulting mixture was filtered, the filtrate was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford the title compound as a yellow solid (280 mg, 70.2%). LCMS m / z = 265 [M+H]+Preparation 71 – 3-(cyanoamino)-1-phenylisoquinoline-4-carbonitrile To a stirred solution of 3-chloro-1-phenylisoquinoline-4-carbonitrile (270 mg, 1.02 mmol) in DMSO (0.5 mL) was added 2-sodioacetonitrile (129 mg, 2.04 mmol) in portions at room temperature. The resulting mixture was stirred for 1 h at 60 °C. The mixture was allowed to cool down to room temperature. The mixture was acidified to pH 3 with 1 mol HCl (aq.) The precipitated solid was collected to afford the title compound (270 mg, crude) as an orange solid. LCMS m / z = 271 [M+H]+Preparation 72 – N3-(1-methylpiperidin-4-yl)-6-phenylpyrimido[4,5-c]isoquinoline-1,3-diamine To a stirred solution of 3-(cyanoamino)-1-phenylisoquinoline-4-carbonitrile (150 mg, 0.555 mmol) in 1,4-dioxane (5.0 mL) was added 1-methylpiperidin-4-amine (126 mg, 1.11 mmol) dropwise at room temperature. The resulting mixture was stirred for 7 h at 100 °C. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in DMSO (5.0 mL). The mixture was acidified to pH 5 with 1M HCl (aq.). Then, the mixture was purified by Prep-HPLCJto afford the title compound as a yellow solid (12.1 mg, 5.6%).1H NMR (400 MHz, Methanol-d4) δ 8.65 (d, J = 8.6 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.99 (t, J = 8.1 Hz, 1H), 7.80 – 7.73 (m, 2H), 7.70 – 7.58 (m, 4H), 4.33 (s, 1H), 3.71 – 3.46 (m, 2H), 3.29 – 3.08 (m, 2H), 2.93 (s, 3H), 2.35 (br., 2H), 2.03 (br. s, 2H). LCMSHm / z = 385 [M+H]+Example 32: N2-(1-methylpiperidin-4-yl)-7-phenoxypyrido[2,3-d]pyrimidine-2,4-diamineTo a stirred solution of 7-chloro-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4- diamine (50.0 mg, 0.171 mmol) and phenol (32.2 mg, 0.342 mmol) in DMSO (1.0 mL) was added t-BuOK (38.3 mg, 0.342 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 2 h. The mixture was allowed to cool down to room temperature. The residuewas purified by Prep-HPLCQto afford the title compound (22.5 mg, 37.6%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 8.6 Hz, 1H), 7.44 (t, J = 7.7 Hz, 3H), 7.31 – 7.10 (m, 4H), 6.74 – 6.39 (m, 2H), 3.81 – 3.64 (m, 1H), 2.68 (d, J = 11.0 Hz, 2H), 2.13 (s, 3H), 1.91 (t, J = 11.4 Hz, 2H), 1.81 – 1.63 (m, 2H), 1.47-1.42 (m, 2H). LCMSHm / z = 351 [M+H]+Example 33: 7-cyclobutoxy-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4- diamineTo a solution of 7-chloro-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamine (50.0 mg, 0.171 mmol) and cyclobutanol (24.6 mg, 0.342 mmol) ,t-BuOK (38.3 mg, 0.342 mmol) in DMSO (2.00 mL) was stirred at 100 °C overnight. The mixture was allowed to cool down to room temperature. The residue was purified by Prep-HPLCBto afford the title compound as a white solid (4.90 mg, 8.74%).1H NMR (400 MHz, DMSO-d6) δ 8.21 – 8.19 (m, 1H), 7.13 (br, 2H), 6.54 (br, 1H), 6.41 – 6.38 (d, J = 12.0, 1H), 5.16 (s, 1H), 3.86 (s, 1H), 2.89 – 2.87 (m, 2H), 2.43 – 2.36 (m, 2H), 2.29 -2.27(m, 5H), 2.09 – 1.99 (m, 2H), 1.91 – 1.74 (m, 3H), 1.68 – 1.55 (m, 3H). LCMS m / z = 329 [M+H]+Example 34: N7-methyl-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4,7- triamineTo a stirred solution of 7-chloro-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4- diamine (30.0 mg, 0.102 mmol) and methanamine hydrochloride (13.8 mg, 0.204 mmol) in DMSO(0.5 mL) was added Cs2CO3 (66.8 mg, 0.204 mmol) in portions at room temperature. The resulting mixture was stirred at 100 °C overnight. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered. The combined filtrate was purified by Prep-HPLCBto afford the title compound (3.40 mg, 9.24%) as a light-yellow oil.1H NMR (400 MHz, Methanol - d4) 7.86 - 7.77 (m, 2H), 6.36 (d, J = 9.0 Hz, 1H), 4.04 - 3.94 (m, 1H), 3.05 - 3.02 (m, 2H), 2.88 (s, 3H), 2.58-2.48 (m, 2H), 2.45 (s, 3H), 2.04 - 2.02 (m, 2H), 1.73-1.60 (m, 2H). LCMSGm / z = 288 [M+H]+Example 35: N2-(1-methylpiperidin-4-yl)-N7-phenylpyrido[2,3-d]pyrimidine-2,4,7- triamineTo a stirred mixture of 7-chloro-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamine (100 mg, 0.342 mmol) and aniline (63.6 mg, 0.684 mmol) in 1,4-dioxane (2.0 mL) were added NaOTMS (76.6 mg, 0.684 mmol), EPhos Pd G4 (31.4 mg, 34.0 μmol) and EPhos (18.3 mg, 34.0 μmol) at room temperature. The resulting mixture was stirred under nitrogen atmosphere at 80 °C for 1 h. The resulted mixture was purified Prep-HPLCAMto afford the title compound (8.8 mg, 7.37%) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.04 (d, J = 8.7 Hz, 1H), 7.95-7.75 (m, 2H), 7.29 (t, J = 7.7 Hz, 2H), 7.03 (s, 2H), 6.94 (t, J = 7.3 Hz, 2H), 6.47 (d, J = 8.7 Hz, 1H), 3.94 – 3.71 (m, 1H), 2.73 (d, J = 11.4 Hz, 2H), 2.16 (s, 3H), 1.96 (t, J = 11.5 Hz, 2H), 1.85 – 1.74 (m, 2H), 1.49 (q, J = 11.5 Hz, 2H). LCMSHm / z = 350 [M+H]+Example 36: N7,N7-dimethyl-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4,7- triamineTo a stirred solution of 7-chloro-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4- diamine (50.0 mg, 0.171 mmol) and dimethylamine hydrochloride (20.6 mg, 0.257 mmol) in DMSO (1.0 mL) at room temperature was added Cs2CO3(111 mg, 0.342 mmol). The resulting mixture was stirred at 100 °C overnight. The mixture was allowed to cool down to room temperature. The crude product was purified by Prep-HPLCALto afford the title compound as a yellow solid (18.1 mg, 33.1%).1H NMR (400 MHz, DMSO-d6) δ 8.01 (dd, J = 9.0, 2.4 Hz, 1H), 6.85 (s, 2H), 6.43 (d, J = 8.9 Hz, 1H), 6.13 (s, 1H), 3.86 – 3.67 (m, 1H), 3.08 (s, 6H), 2.78 – 2.66 (m, 2H), 2.15 (s, 3H), 1.95 (t, J = 10.8 Hz, 2H), 1.78 (d, J = 12.8 Hz, 2H), 1.59 – 1.36 (m, 2H). LCMSHm / z = 302 [M+H]+Example 37: N2-(2-(isoindolin-2-yl)ethyl)-5,7-dimethylpyrido[2,3-d]pyrimidine-2,4- diamineAs described for Example 29, using isoindoline and purification by Prep-HPLCOto afford the title compound as white solid (5.6 mg, 5.78%).1H NMR (400 MHz, DMSO-d6) δ 7.31 – 7.07 (m, 4H), 6.77-6.45 (m, 4H), 3.91 (s, 4H), 3.49 - 3.46 (m, 2H), 2.86 (t, J = 6.7 Hz, 2H), 2.64 (s, 3H), 2.38 (s, 3H). LCMSHm / z = 335 [M+H]+Example 38: 7-isopropoxy-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4- diamineTo a solution of 7-chloro-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamine (50.0 mg, 0.171 mmol) and isopropyl alcohol (1.00 mL, 13 mmol) ,Cs2CO3 (111 mg, 0.342 mmol) in DMSO (1.00 mL) was stirred at 100 °C overnight. The mixture was allowed to cool down to room temperature. The crude product was purified by Prep-HPLCALto afford the title compound as a white solid (6.50 mg, 12.0%).1H NMR (400 MHz, DMSO-d6) δ 8.18 – 8.16 (d, J = 8.00, 1H), 7.09 (m, 2H), 6.36 – 6.33 (m, 2H), 5.78 (br m, 1H), 3.79 (s, 1H), 3.74 – 3.71 (d, J = 12.0, 2H), 2.16 (s, 3H), 1.98 – 1.93 (m, 2H), 1.79 – 1.77 (m, 2H), 1.54 – 1.46 (m, 2H), 1.33 (d, J = 16.0, 6H). LCMSCm / z: 317 [M+H]+Example 39: N4-methyl-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diaminePreparation 73 – 2-chloro-N-methylpyrido[2,3-d]pyrimidin-4-amine To a stirred solution of 2,4-dichloropyrido[2,3-d]pyrimidine (500 mg, 2.50 mmol) and methanamine hydrochloride (338 mg, 5.00 mmol) in DMSO (5.0 mL) at room temperature was added Cs2CO3 (1.63 g, 5.00 mmol). The resulting mixture was stirred at 60 °C for 1 h. The resulting mixture was diluted with water (5 mL). The precipitated solids were collected by filtration and washed with water. This resulted in the title compound as a white solid (330 mg, crude). LCMS m / z = 195 [M+H]+Preparation 74 – N4-methyl-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamine To a stirred solution of 2-chloro-N-methylpyrido[2,3-d]pyrimidin-4-amine (150 mg, 0.771 mmol) in dioxane (3.0 mL) at room temperature was added 1-methylpiperidin-4-amine (176 mg, 1.54 mmol). The resulting mixture was stirred at 100 °C overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLCAKto afford the title compound as a white solid (4.0 mg, 1.71%).1H NMR (400 MHz, DMSO-d6) δ 8.57 (dd, J = 4.5, 1.9 Hz, 1H), 8.27 (dd, J = 8.0, 2.0 Hz, 1H), 8.02 (s, 1H), 7.13 – 6.91 (m, 1H), 6.69 (s, 1H), 3.93 – 3.72 (m, 1H), 2.94 (d, J = 4.4 Hz, 3H), 2.83 – 2.67 (m, 2H), 2.16 (s, 3H), 1.95 (td, J = 11.8, 2.5 Hz, 2H), 1.83 (d, J = 12.3 Hz, 2H), 1.62 – 1.46 (m, 2H). LCMSGm / z = 273 [M+H]+Example 40: N4,N4-dimethyl-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4- diaminePreparation 75 – 2-chloro-N,N-dimethylpyrido[2,3-d]pyrimidin-4-amine To a stirred solution of 2,4-dichloropyrido[2,3-d]pyrimidine (300 mg, 1.50 mmol) and dimethylamine hydrochloride (245 mg, 3.00 mmol) in DMSO (5.0 mL) was added Cs2CO3 (977 mg, 3.00 mmol) at room temperature. The resulting mixture was stirred at 60 °C for 1 h. The resulting mixture was diluted with water (5.0 mL). The residue was purified by Prep-HPLCBto afford the title compound (180 mg, 57.5%). LCMS m / z = 209 [M+H]+Preparation 76 – N4,N4-dimethyl-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4- diamine To a stirred solution of 2-chloro-N,N-dimethylpyrido[2,3-d]pyrimidin-4-amine (80.0 mg, 0.383 mmol) in dioxane (2.0 mL) at room temperature was added 1-methylpiperidin-4-amine (87.6 mg, 0.766 mmol). The resulting mixture was stirred at 100 °C overnight. The mixture was allowed to cool down to room temperature. The crude product was purified by Prep-HPLCAKto afford the title compound as an off-white solid (31.9 mg, 26.9%).1H NMR (400 MHz, DMSO- d6) δ 8.62 (s, 1H), 8.33 (s, 1H), 7.06 (s, 2H), 4.07 (s, 1H), 3.42 - 3.20 (m, 8H), 3.14 - 2.99 (m, 2H), 2.70 (s, 3H), 2.19 - 2.03 (m, 2H), 1.92 - 1.72 (m, 2H). LCMSQm / z = 287 [M+H]+Example 41: N7-(2,4-dimethoxybenzyl)-N2-(1-methylpiperidin-4-yl)pyrido[2,3- d]pyrimidine-2,4,7-triamineTo a stirred solution of 7-chloro-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4- diamine (300 mg, 1.03 mmol) and (2,4-dimethoxyphenyl)methanamine (514 mg, 3.08 mmol) in DMSO (8.0 mL) at room temperature was added Cs2CO3(1.02 g, 3.08 mmol). The resulting mixture was stirred at 120 °C for 5 h. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLCBto afford titled product (78 mg, 17.90%) as a green solid.1H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 8.8 Hz, 1H), 7.24 - 7.09 (m, 2H), 6.83 (s, 2H), 6.56 (d, J = 2.4 Hz, 1H), 6.46 (dd, J = 8.3, 2.4 Hz, 1H), 6.26 (d, J = 8.7 Hz, 1H), 6.10 (s, 1H), 4.42 (d, J = 5.6 Hz, 2H), 3.82 - 3.73 (m, 7H), 2.76 - 2.67 (m, 2H), 2.15 (s, 3H), 2.00 - 1.90 (m, 2H), 1.81 – 1.73 (m, 2H), 1.52 – 1.41 (m, 2H). LCMSH m / z = 424 [M+H]+Example 42: N2-(1-methylpiperidin-4-yl)-6-(prop-1-yn-1-yl)pyrido[2,3-d]pyrimidine-2,4- diamineTo a stirred mixture of 6-bromo-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4- diamine (40.0 mg, 0.119 mmol) and tributyl(prop-1-yn-1-yl)stannane (39.0 mg, 0.119 mmol) in toluene (0.5 mL) at room temperature was added Pd(PPh3)4 (6.85 mg, 0.006 mmol,) under nitrogen atmosphere. The resulting mixture was stirred at 100 °C overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLCB. The crude product was further purified by Prep-HPLCATto fford the title compound as an off-white solid (7.2 mg, 20.3%).1H NMR (400 MHz, DMSO- d6) δ 8.56 (d, J = 2.3 Hz, 1H), 8.43(s, 1H), 7.79 - 7.29 (br, 2H), 7.71 – 6.68 (br, 1H), 3.91 – 3.71 (m, 1H), 2.81 (d, J = 11.1 Hz, 2H), 2.22 (s, 3H), 2.15 – 1.94 (m, 5H), 1.87 – 1.74 (m, 2H), 1.61 - 1.48 (m, 2H). LCMSHm / z = 297 [M+H]+Example 43: N2-(1-methylpiperidin-4-yl)-1,8-naphthyridine-2,4-diaminePreparation 77 – 4-chloro-N-(1-methylpiperidin-4-yl)-1,8-naphthyridin-2-amine and 2-chloro- N-(1-methylpiperidin-4-yl)-1,8-naphthyridin-4-amine. A solution of 2,4-dichloro-1,8-naphthyridine (2.00 g, 10.0 mmol), 1-methylpiperidin-4-amine (13.3 mL, 12.1 mmol) and DIEA (3.50 mL, 20.1 mmol) in DMSO (10.0 mL) was stirred at 40 °C for 1 h. The resulting mixture was purified by Prep-HPLCBto afford 4-chloro-N-(1- methylpiperidin-4-yl)-1,8-naphthyridin-2-amine (1.62 g, 58.7%) and 2-chloro-N-(1- methylpiperidin-4-yl)-1,8-naphthyridin-4-amine (1.16 g, 42.0%) as a yellow solid. LCMS m / z = 277 [M+H]+Preparation 78 – 4-((diphenylmethylene)amino)-N-(1-methylpiperidin-4-yl)-1,8-naphthyridin- 2-amine To a stirring solution of 4-chloro-N-(1-methylpiperidin-4-yl)-1,8-naphthyridin-2-amine (1.00 g, 3.61 mmol) and diphenylmethanimine (727 µL, 4.33 mmol) in 1,4-dioxane (10.0 mL) were added Pd(OAc)2 (81.1 mg, 0.361 mmol), XantPhos (209 mg, 0.361 mmol) and Cs2CO3 (2.35 g, 7.23 mmol). The mixture was stirred under nitrogen atmosphere at 100 °C for 1 h. The resulting mixture was filtered through a short pad of Celite. The pad was washed with CH2Cl2 (3 × 20 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford the title compound (1.1 g, 72.4%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.53 (dd, J = 4.4, 1.9 Hz, 1H), 8.28 (dd, J = 8.0, 2.0 Hz, 1H), 7.02 (dd, J = 8.0, 4.4 Hz, 1H), 6.80 (d, J = 7.7 Hz, 1H), 6.49 (s, 2H), 5.86 (s, 1H), 3.90 (s, 1H), 2.90 - 2.75 (m, 2H), 2.26 (s, 3H), 2.22 - 2.02 (m, 2H), 1.92 (m, 2H), 1.58 – 1.43 (m, 2H). LCMSHm / z = 258 [M+H]+. Example 44: 5-methyl-N2-(quinuclidin-4-yl)-7,8-dihydro-6H-cyclopenta[5,6]pyrido[2,3- d]pyrimidine-2,4-diaminePreparation 79 – 1-azabicyclo[2.2.2]octan-4-amine hydrochloride To a solution of 1-aza bicyclo[2.2.2]octane-4-carboxylic acid hydrochloride (200 mg, 1.04 mmol) in toluene (2 mL) was added Et3N (211 mg, 2.09 mmol) and DPPA (0.250 mL, 1.15mmol) under nitrogen atmosphere at room temperature. The mixture was stirred under nitrogen atmosphere at room temperature for 2 h. The resulting mixture was heated to 100 °C and stirred for additional 3 h. The mixture was allowed to cool down to room temperature and quenched by the addition of conc. HCl (6.00 mL) dropwise at 0°C. The mixture was extracted with EtOAc (3x10 mL). The combined organic phases were concentrated under reduced pressure. Then residue was purified by Prep-HPLCLto afford the title compound as a white semi-solid (500 mg, crude). LCMS m / z =125 [M-H]- Preparation 80 – 5-methyl-N2-(quinuclidin-4-yl)-7,8-dihydro-6H-cyclopenta[5,6]pyrido[2,3- d]pyrimidine-2,4-diamine To a solution of N-(3-cyano-4-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)cyanamide (40.0 mg, 0.202 mmol) and 1-azabicyclo[2.2.2]octan-4-amine hydrochloride (197 mg, 1.21 mmol) in EtOH (1.0 mL) was added Et3N (40.8 mg, 0.404 mmol). The reaction mixture was stirred at 100 °C overnight. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The crude product (150 mg) was purified by Prep- HPLCMto afford the title compound as a white solid (8.1 mg, 12.4%).1H NMR (400 MHz, DMSO-d6) δ 6.60 (s, 2H), 5.77 (s, 1H), 2.90 - 2.80 (m, 10H), 2.58 (s, 3H), 2.08 - 1.98 (m, 2H), 1.94 (t, J = 7.8 Hz, 6H). LCMSLm / z = 325 [M+H]+Example 45: N3-(1-methylpiperidin-4-yl)-6-phenyl-8,9-dihydro-7H- cyclopenta[4,5]pyrido[2,3-d]pyrimidine-1,3-diaminePreparation 81 – 1,3-dihydroxy-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitrile To a stirred solution of ethyl 2-oxocyclopentane-1-carboxylate (5.00 g, 32.0 mmol) in MeOH (25.0 mL) were added cyanoacetamide (2.83 g, 33.6 mmol) and KOH (1.89 g, 33.6 mmol). The resulting mixture was stirred at 70 °C for 1 h. The mixture was allowed to cool down to room temperature. The mixture was acidified to pH 1 with aq. HCl (1.0 M). The precipitated solids were collected by filtration and washed with water (3 × 50 mL). The solid was dried under vacuum to afford the title compound (1.68 g crude) as a white solid. LCMS m / z = 177 [M+H]+. Preparation 82 – 4-cyano-6,7-dihydro-5H-cyclopenta[c]pyridine-1,3-diyl bis(trifluoromethanesulfonate)To a mixture of 1,3-dihydroxy-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitrile (600 mg, 3.40 mmol) and DIEA (1.32 g, 10.2 mmol) in DCM (10.0 mL) were added Tf2O (2.88 g, 10.2 mmol) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 1 h and quenched by the addition of H2O (30 mL). The mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford the title compound as an off-white liquid (1.30 g, crude). LCMS m / z = 439 [M-H]- Preparation 83 – 4-cyano-1-phenyl-6,7-dihydro-5H-cyclopenta[c]pyridin-3-yl trifluoromethanesulfonate To a mixture of 4-cyano-6,7-dihydro-5H-cyclopenta[c]pyridine-1,3-diyl bis(trifluoromethanesulfonate) (1.20 g, 2.72 mmol) and phenyl boronic acid (270 mg, 2.18 mmol,) in dioxane (12.0 mL) and H2O (4.0 mL) were added Pd(dppf)Cl2∙CH2Cl2(190 mg, 0.273 mmol,) and K3PO4(1.16 g, 5.45 mmol). The resulting mixture was stirred under nitrogen atmosphere at room temperature for 1 h. The resulting mixture was diluted with in H2O (30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford the title compound as a white solid (310 mg, 30.8%). LCMS m / z = 369 [M+H]+Preparation 84 – N-(4-cyano-1-phenyl-6,7-dihydro-5H-cyclopenta[c]pyridin-3-yl)cyanamide To a mixture of 4-cyano-1-phenyl-6,7-dihydro-5H-cyclopenta[c]pyridin-3-yl trifluoromethanesulfonate (300 mg, 0.814 mmol) and cyanamide (68.4 mg, 1.62 mmol) in 1,4- dioxane (5.0 mL) were added Brettphos Pd G3 (73.8 mg, 0.081 mmol), Brettphos (43.7 mg, 0.081 mmol) and Cs2CO3 (530 mg, 1.62 mmol) at room temperature. The resulting mixture was stirred under nitrogen atmosphere at 100 °C for 1 h. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered through a short pad of Celite. The pad was washed with MeOH (20 mL×3). The combined filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLCCto afford the title compound (150 mg, 70.7%) as a yellow solid. LCMS m / z = 261 [M+H]+Preparation 85 – N3-(1-methylpiperidin-4-yl)-6-phenyl-8,9-dihydro-7H- cyclopenta[4,5]pyrido[2,3-d]pyrimidine-1,3-diamine. To a mixture of N-(4-cyano-1-phenyl-6,7-dihydro-5H-cyclopenta[c]pyridin-3-yl)cyanamide (60.0 mg, 0.231 mmol) and 1-methylpiperidin-4-amine (52.6 mg, 0.462 mmol) in 1,4-dioxane (3.0 mL) was stirred at 60 °C overnight. The resulting mixture was allowed to cool down toroom temperature and concentrated under reduced pressure. The crude product was purified by Prep-HPLCABto afford the title compound as a light-yellow solid (11.6 mg, 13.4%).1H NMR (400 MHz, DMSO-d6) δ 7.79-7.77 (m, 2H), 7.55 – 7.40 (m, 3H), 6.71 (br, 2H), 6.38 (br, 1H), 3.89 – 3.75 (m, 1H), 3.45 – 3.36 (m, 2H), 3.00 (t, J = 8.0 Hz, 2H), 2.74 (d, J = 12.0 Hz, 2H), 2.16 (s, 3H), 2.13 – 2.03 (m, 2H), 1.96 (t, J = 12.0 Hz, 2H), 1.86 – 1.76 (m, 2H), 1.60 – 1.45 (m, 2H). LCMSHm / z: 375 [M+H]+Example 46: 6-methyl-N3-(3-morpholinopropyl)-8,9-dihydro-7H- cyclopenta[4,5]pyrido[2,3-d]pyrimidine-1,3-diamineA solution of N-(4-cyano-1-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-3-yl)cyanamide (60.0 mg, 0.30 mmol) and 4-morpholinepropanamine (43.7 µL, 0.30 mmol) in EtOH (1.20 mL) was stirred at 80 ℃ overnight. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by Prep-HPLCVto afford the title compound as white solid (33.0 mg, 31.8%).1H NMR (400 MHz, DMSO-d6) δ 6.58-6.54 (m, 3H), 3.58-3.56 (m, 4H), 3.31-3.28 (m, 4H), 2.83-2.79 (m, 2H), 2.51-2.31 (m, 9H), 2.15- 2.09 (m, 2H), 1.72-1.65 (m, 2H). LCMSOm / z = 343 [M+H]+Example 47: 5-methyl-N2-(3-morpholinopropyl)-7,8-dihydro-6H- cyclopenta[5,6]pyrido[2,3-d]pyrimidine-2,4-diamineTo a solution of N-(3-cyano-4-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)cyanamide (60.0 mg, 0.303 mmol) in EtOH (1.00 mL) was added 4-morpholinepropanamine (43.7 uL, 0.303 mmol) at room temperature. The resulting mixture was stirred overnight at 80 °C. The mixture was allowed to cool down to room temperature. The crude product was purified by Prep-HPLCNto afford the title compound as white solid (17.1 mg, 16.5%).1H NMR (400 MHz, DMSO-d6) δ 6.84-6.32 (br, 3H), 3.57 (t, J = 4.7 Hz, 4H), 3.30 (t, J = 8.0 Hz, 2H), 2.88- 2.82 (m, 4H), 2.57 (s, 3H), 2.33-2.30 (m, 6H), 2.02-2.01 (m, 2H), 1.68 -1.64 (m, 2H). LCMSHm / z = 343 [M+H]+Example 48: 6-chloro-5-methyl-N2-(1-methylpiperidin-4-yl)-7-phenylpyrido[2,3- d]pyrimidine-2,4-diaminePreparation 86 – 2-hydroxy-6-methyl-4-phenylpyridine-3-carbonitrile To a solution of 3-oxo-3-phenylpropanal (5.00 g, 30.8 mmol) in EtOH (50.0 mL) was added cyanoacetamide (2.59 g, 30.8 mmol) and 1,4-diazabicyclo[2.2.2]octane (34.6 g, 308 mmol) dropwise at room temperature. The resulting mixture was stirred for 6 h at 80 °C. The mixture was allowed to cool down to room temperature. The resulting mixture was stirred overnight at room temperature. The precipitated solids were collected by filtration and washed with MeCN (3 mL) to afford the title compound as white solid (3.20 g, crude). LCMS m / z = 211 [M+H]+Preparation 87 – 5-chloro-2-hydroxy-6-methyl-4-phenylpyridine-3-carbonitrile To a solution of 2-hydroxy-6-methyl-4-phenylpyridine-3-carbonitrile (1.00 g, 4.76 mmol) in THF (5.00 mL) and MeOH (5.00 mL) was added NCS (0.950 g, 7.14 mmol) at room temperature. The resulting mixture was stirred for 1 h at 40 °C. The mixture was allowed to cool down to room temperature. The precipitated solids were collected by filtration and washed with PE (10 mL). The solid was purified by silica gel column chromatography, eluted with CH2Cl2to afford the title compound as light-yellow solid (780 mg, 67.0%). LCMS m / z = 245 [M+H]+Preparation 88 – 5-chloro-3-cyano-6-methyl-4-phenylpyridin-2-yl trifluoromethanesulfonate To a solution of 5-chloro-2-hydroxy-6-methyl-4-phenylpyridine-3-carbonitrile (770 mg, 3.15 mmol) in DCM (7.00 mL) was added Et3N (0.870 mL, 6.29 mmol) and Tf2O (1.06 mL, 6.29 mmol) dropwise at 0 °C. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was extracted with CH2Cl2(3 x 10 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (27:73) to afford the title compound as yellow solid (910 mg, 76.8%). LCMS m / z = 375 [M-H]- Preparation 89 – 5-chloro-2-(cyanoamino)-6-methyl-4-phenylpyridine-3-carbonitrileTo a stirred mixture of 5-chloro-3-cyano-6-methyl-4-phenylpyridin-2-yl trifluoromethanesulfonate (500 mg, 1.33 mmol) and cyanamide (223 mg, 5.31 mmol) in 1,4- dioxane (6.50 mL) was added XantPhos (120 mg, 0.133 mmol), Pd2(dba)3(71.2 mg, 0.133 mmol) and DIEA (865 mg, 2.65 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 120 °C under nitrogen atmosphere for 1 h. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (6:1) to afford the title compound as yellow oil (200 mg, 56.1%). LCMS m / z = 269 [M+H]+Preparation 90 – 6-chloro-5-methyl-N2-(1-methylpiperidin-4-yl)-7-phenylpyrido[2,3- d]pyrimidine-2,4-diamine To a solution of 5-chloro-2-(cyanoamino)-6-methyl-4-phenylpyridine-3-carbonitrile (150 mg, 0.558 mmol) in 1,4-dioxane (1.50 mL) was added 1-methylpiperidin-4-amine (76.5 mg, 0.670 mmol,) at room temperature. The resulting mixture was stirred for 1 h at 100 °C. The mixture was allowed to cool down to room temperature. The residue was purified by trituration with DMF (4 mL) to afford the title compound as white solid (19.4 mg, 9.08%).1H NMR (400 MHz, DMSO-d6) δ 7.60 -7.59 (m, 2H), 7.52 – 7.43 (m, 3H), 7.01 (br, 2H), 6.67 (br, 1H), 3.79 (br, 1H), 2.80 (s, 3H), 2.74 (d, J = 8.3 Hz, 2H), 2.15 (s, 3H), 1.93 (t, J = 11.3 Hz, 2H), 1.79 (d, J = 12.6 Hz, 2H), 1.52-1.50 (m, 2H). LCMSPm / z = 383 [M+H]+Example 49: N2-(1-methylpiperidin-4-yl)-7-(m-tolyl)pyrido[2,3-d]pyrimidine-2,4-diamineTo a stirred mixture of Example 23 (40 mg, 0.137 mmol) in 1,4-Dioxane / H2O (5 / 1, 2mL) at room temperature was added 3-methylphenylboronic acid (20.4 mg, 0.151 mmol), CataCXium-A-Pd-G3 (5 mg, 0.007 mmol), CataCXium (6 mg, 0.017 mmol) and K3PO4(87 mg, 0.411 mmol). The resulting mixture was stirred for 6 h at 100 °C under nitrogen atmosphere. The solution was cooled to room temperature and treated with mercaptoalkyl functionalized silica scavenger and then filtered. The filtrate was purified by Agela MP-Flash200Libraryto afford the title compound as a solid (13.7 mg, 27.46%).1H NMR (300 MHz, DMSO-d6) δ 8.42 (d, J = 8.3 Hz, 1H), 8.01 (s, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.50 – 7.23 (m, 4H),6.58 (s, 1H), 3.99-3.70 (m, 1H), 2.85 – 2.69 (m, 2H), 2.43 (s, 3H), 2.18 (s, 3H), 2.09 – 1.92 (m, 2H), 1.90 – 1.76 (m, 2H), 1.64 – 1.44 (m, 2H). LCMSLibrary G: m / z = 349 [M+H]+. Example 50 – Example 114The following Examples were synthesised in a similar manner to that described for Example 49, using the appropriate boronic acid or ester reagent: E 1 LCMS E E E E E E+E E E E E E E E+E E E E E E EE E E E E EE E E E E E2H).E E E E E E EE E E E E E EE E E E E E E2H).E E E E E E E. . , , . , 3H), 2.16 (s, 3H), 2.02 – 1.88(m, 2H), 1.87 – 1.76 (m, 2H), E E E EExample 115: 7-(2-chlorophenyl)-N2-(1-methylpiperidin-4-yl) pyrido[2,3-d] pyrimidine- 2,4-diamineTo a stirred mixture of Example 23 (40 mg, 0.137 mmol) in 1,4-Dioxane / H2O (5 / 1, 2 mL) at room temperature was added 2-chlorophenylboronic acid (23.5 mg, 0.151 mmol), Xphos G2 (5 mg, 0.006 mmol) and K3PO4 (87.00 mg, 0.411 mmol). The resulting mixture was stirred for 6 h at 110 °C under nitrogen atmosphere. The solution was cooled to room temperature and treated with mercaptoalkyl functionalized silica scavenger and then filtered. The filtrate was purified by Agela MP-Flash200Libraryto afford the title compound as a solid (3.3 mg, 6.55%). LCMSLibrary C: m / z = 369 [M+H]+. Example 116 – Example 118The following Examples were synthesised in a similar manner to that described for Example 115, using the appropriate boronic acid or ester reagent: E 1 LCMS E E E .Example 119: N2-(1-methylpiperidin-4-yl)-7-(oxazol-2-yl)pyrido[2,3-d]pyrimidine-2,4- diamineTo a stirred mixture of Example 23 (40 mg, 0.137 mmol) in Toluene (2 mL) at room temperature was added 2-(tributylstannyl)-1,3-oxazole (53.82 mg, 0.151 mmol) and Pd(PPh3)4 (5 mg, 0.004 mmol). The resulting mixture was stirred for 6 h at 110 °C under nitrogen atmosphere. The solution was cooled to room temperature and treated with mercaptoalkyl functionalized silica scavenger and then filtered. The filtrate was purified by Agela MP- Flash200Libraryto afford the title compound as a solid (3.9 mg, 8.77%). LCMSLibrary C: m / z = 326 [M+H]+.Example 120: 5-methyl-N2-(3-morpholinopropyl)-7-phenylpyrido[2,3-d]pyrimidine-2,4- diaminePreparation 91 – 2-chloro-4-methyl-6-phenylnicotinonitrile To a solution of 2,6-dichloro-4-methylnicotinonitrile (20.0 g, 107 mmol) and phenyl boronic acid (10.4 g, 85.6 mmol) in 1,4-dioxane (150 mL) and H2O (150 mL) at room temperature were added Pd(dppf)Cl2(7.82 g, 10.7 mmol) and K3PO4(45.4 g, 214 mmol). The resulting mixture was stirred under nitrogen atmosphere at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The resulting mixture was filtered, the filter cake was washed with water (3 × 50 mL). The solid was purified by trituration with MeOH (3 × 100 mL) to afford title compound (22.3 g, crude) as a reddish solid. LCMS m / z = 229 [M+H]+Preparation 92 – N-(3-cyano-4-methyl-6-phenylpyridin-2-yl)cyanamide To a solution of 2-chloro-4-methyl-6-phenylnicotinonitrile (2.00 g, 8.75 mmol), Cs2CO3 (5.70 g, 17.5 mmol) and cyanamide (0.740 g, 17.5 mmol) in 1,4-dioxane (30.0 mL) at room temperature were added Brettphos Pd G3 (0.790 g, 0.875 mmol) and Brettphos (0.470 g, 0.875 mmol). The mixture was stirred under nitrogen atmosphere at 100 °C for 2 h. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with DCM (3 × 100 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by HPLCBto afford the title compound (600 mg, 29.30%) as a yellow green solid. LCMS m / z = 235 [M+H]+. Preparation 93 – 5-methyl-N2-(3-morpholinopropyl)-7-phenylpyrido[2,3-d]pyrimidine-2,4- diamine To a solution of N-(3-cyano-4-methyl-6-phenylpyridin-2-yl)cyanamide (100 mg, 0.427 mmol) in EtOH (2.0 mL) at room temperature was added 3-morpholinopropan-1-amine (185 mg, 1.28 mmol). The resulting mixture was stirred at 100 °C for 2 h. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by Prep-HPLCAFto afford the title compound (72.8 mg, 45.10%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.19 - 8.11 (m, 2H), 7.55 - 7.40 (m, 4H), 7.04 - 6.51 (m, 3H), 3.59 (t, J = 4.6 Hz, 4H), 3.41 - 3.36 (m, 2H), 2.77 (s, 3H), 2.41 - 2.30 (m, 6H), 1.77 - 1.65 (m, 2H). LCMSCm / z = 379 [M+H]+Example 121: 5,6,7-trimethyl-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4- diaminePreparation 94 – N-(3-cyano-4,5,6-trimethylpyridin-2-yl)cyanamide. A solution of 2-chloro-4,5,6-trimethylnicotinonitrile (200 mg, 1.10 mmol) and cyanamide, monosodium salt (141 mg, 2.21 mmol) in DMSO (0.5 mL) was stirred at 100 °C for 2 h. The mixture was allowed to cool down to room temperature. The residue was purified by Prep- HPLCBto afford the title compound as a light-yellow solid (110 mg, 53.3%). LCMS m / z = 187 [M+H]+Preparation 95 – 5,6,7-trimethyl-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4- diamine. A solution of N-(3-cyano-4,5,6-trimethylpyridin-2-yl)cyanamide (90.0 mg, 0.483 mmol) and 1- methylpiperidin-4-amine (110 mg, 0.966 mmol) in EtOH (5.00 mL) was stirred at 100 °C for 2.5 h. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLCAUto afford the title compound as a white solid (78.7 mg, 54.2%).1H NMR (400 MHz, DMSO-d6) δ 6.68 (br, 2H), 6.23 (br, 1H), 3.81 – 3.68 (m, 1H), 2.74-2.72 (m, 2H), 2.57 (s, 3H), 2.44 (s, 3H), 2.17 (s, 3H), 2.16 (s, 3H), 1.96-1.91 (m, 2H), 1.81-1.78 (m, 2H), 1.57 – 1.42 (m, 2H). LCMSCm / z = 301 [M+H]+Example 122: methyl 4-amino-2-[(1-methylpiperidin-4-yl)amino]pyrido[2,3- d]pyrimidine-6-carboxylateTo a stirred solution of Example 20 (1.50 g, 4.45 mmol) in MeOH (200 mL) and DMF (4.0 mL) were added Pd(dppf)Cl2.CH2Cl2 (362 mg, 0.445 mmol) and Et3N (1.24 mL, 8.90 mmol). The resulting mixture was stirred under carbon monoxide atmosphere (10 atm) at 100 °C overnight. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with MeOH (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLCBto afford the title compound(900 mg, 63.8%) as a brown solid.1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.96 (s, 1H), 7.75 (br, 2H), 7.35 – 7.00 (m, 1H), 3.87 (s, 3H), 3.86-3.83 (m, 1H), 2.75-2.73 (m, 2H), 2.16 (s, 3H), 1.96-1.91 (m, 2H), 1.85 – 1.72 (m, 2H), 1.61 – 1.39 (m, 2H). LCMSCm / z = 317 [M+H]+Example 123: {4-amino-2-[(1-methylpiperidin-4-yl)amino]pyrido[2,3-d]pyrimidin-6- yl}methanol.To a stirred mixture of Example 122 (200 mg, 0.632 mmol) in THF (4.0 mL) was added LiAlH4(474 µL, 0.948 mmol, 2.0 M in THF) dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 1 h. The reaction was quenched with water at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLCAUto afford the title compound (22.8 mg, 12.5%) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.29 (s, 1H), 7.37 (br, 2H), 6.52 (br, 1H), 5.22 (t, J = 5.4 Hz, 1H), 4.50 (d, J = 5.2 Hz, 2H), 3.98 – 3.61 (m, 1H), 2.79 – 2.70 (m, 2H), 2.16 (s, 3H), 1.99 – 1.89 (m, 2H), 1.86 – 1.78 (m, 2H), 1.65 – 1.32 (m, 2H). LCMSCm / z = 289 [M+H]+Example 124: 5-methyl-7-phenyl-N2-(quinuclidin-4-yl)pyrido[2,3-d]pyrimidine-2,4- diamineTo a stirred solution of N-(3-cyano-4-methyl-6-phenylpyridin-2-yl)cyanamide (50.0 mg, 0.213 mmol) in EtOH (1.0 mL) were added quinuclidin-4-amine hydrochloride (160 mg, 1.28 mmol) and Et3N (534 uL, 3.84 mmol). The resulting mixture was stirred at 100 °C for 4 days. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLCASto afford the title compound (19.4 mg, 25.30%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.19 - 8.10 (m, 2H), 7.56 – 7.46 (m, 3H), 7.43 (s, 1H), 6.86 (s, 2H), 6.06 (s, 1H), 2.96 - 2.82 (m, 6H), 2.77 (s, 3H), 2.07 - 1.87 (m, 6H). LCMSOm / z = 361 [M+H]+Example 125: 1-{4-amino-2-[(1-methylpiperidin-4-yl)amino]pyrido[2,3-d]pyrimidin-6- yl}ethenone.To a stirred solution of Example 20 (600 mg, 1.78 mmol) and tributyl(1- ethoxyethenyl)stannane (1.29 g, 3.56 mmol) in DMF (9.0 mL) was added Pd(PPh3)4(206 mg, 0.178 mmol). The resulting mixture was stirred under nitrogen atmosphere at 100 °C overnight. The mixture was allowed to cool down to room temperature. To the above mixture was added aq. HCl (1.0 M, 9.0 mL) at room temperature and stirred for additional 1 h at room temperature. The mixture was basified pH 9 with saturated NaHCO3(aq.). and extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Prep-HPLCBto afford the title compound (400 mg, 74.7%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.95 (s, 1H), 7.76 (br, 2H), 7.39 – 6.95 (m, 1H), 4.02 – 3.72 (m, 1H), 2.77-2.74 (m, 2H), 2.56 (s 3H), 2.16 (s, 3H), 1.97-1.94 (m, 2H), 1.81-1.79 (m, 2H), 1.57-1.49 (m, 2H). LCMSHm / z = 301 [M+H]+Example 126: 1-{4-amino-2-[(1-methylpiperidin-4-yl)amino]pyrido[2,3-d]pyrimidin-6- yl}ethanolTo a stirred solution of Example 125 (150 mg, 0.499 mmol) in MeOH (3.0 mL) was added NaBH4 (37.8 mg, 0.999 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine, filtered and concentrated under reduce pressure. The residue was purified by Prep-HPLCASto afford the title compound (20.4 mg, 13.5%) as an off-white solid.1H NMR (400 MHz, DMSO- d6) δ 8.60 (s, 1H), 8.30 (s, 1H), 7.38 (br, 2H), 6.48 (br, 1H), 5.25 (d, J = 4.0 Hz, 1H), 4.78 – 4.75 (m, 1H), 3.80 – 3.79 (m, 1H), 2.75 – 2.72 (m, 2H), 2.16 (s, 3H), 1.99 – 1.89 (m, 2H), 1.86 – 1.77 (m, 2H), 1.60 – 1.42 (m, 2H), 1.40 (d, J = 6.4 Hz, 3H). LCMSHm / z = 303 [M+H]+Example 127: 6-phenyl-N3-(quinuclidin-4-yl)-8,9-dihydro-7H-cyclopenta[4,5]pyrido[2,3- d]pyrimidine-1,3-diamineTo a stirred solution of N-(4-cyano-1-phenyl-6,7-dihydro-5H-cyclopenta[c]pyridin-3- yl)cyanamide (30 mg, 0.115 mmol) and quinuclidin-4-amine hydrochloride (87.2 mg, 0.690 mmol) in EtOH (1.0 mL) at room temperature was added Et3N (175 mg, 1.73 mmol). The resulting mixture was stirred at 100°C for 30 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLCBto afford the title compound (5.3 mg, 10.67%) as a white solid formate salt.1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.82 - 7.72 (m, 2H), 7.54 - 7.41 (m, 3H), 6.78 (br, 2H), 6.23 (br, 1H), 3.40 - 3.35 (m, 2H), 3.10 - 2.96 (m, 8H), 2.18 - 2.10 (m, 8H). LCMSRm / z = 387 [M+H]+Example 128: 6-chloro-5-methyl-N2-(3-morpholinopropyl)-7-phenylpyrido[2,3- d]pyrimidine-2,4-diamineA solution of Example 120 (25.0 mg, 0.066 mmol) and 1-chloropyrrolidine-2,5-dione (26.5 mg, 0.198 mmol) in THF (1.0 mL) and MeOH (1.0 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in water (5 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLCGto afford the title compound (3.3 mg, 12.1%) as a yellow solid.1H NMR (400 MHz, Methanol-d4) δ 7.68 - 7.60 (m, 2H), 7.51 - 7.41 (m, 3H), 3.70 (t, J = 4.7 Hz, 4H), 3.48 (t, J = 6.8 Hz, 2H), 2.89 (s, 3H), 2.53 - 2.43 (m, 6H), 1.89 - 1.77 (m, 2H). LCMSCm / z = 413 [M+H]+Example 129: N3-(3-morpholinopropyl)-6-phenyl-8,9-dihydro-7H- cyclopenta[4,5]pyrido[2,3-d]pyrimidine-1,3-diaminePreparation 96 – 1,3-dihydroxy-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitrileTo a stirred solution of ethyl 2-oxocyclopentane-1-carboxylate (25.0 g, 160 mmol) in MeOH (125 mL) were added cyanoacetamide (14.1 g, 168 mmol) and KOH (9.43 g, 168 mmol, 1.05 equiv). The resulting mixture was stirred at 70 °C for 1 h. The mixture was allowed to cool down to room temperature and acidified to pH 1 with HCl (aq.1 M). The precipitated solids were collected by filtration and washed with water (200 mL). The resulting solid was dried under vacuum to afford the title compound (9.5 g, 33.6%) as a white solid. Preparation 97 – 4-cyano-6,7-dihydro-5H-cyclopenta[c]pyridine-1,3-diyl bis(trifluoromethanesulfonate) To a solution of 1,3-dihydroxy-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitrile (4.00 g, 22.7 mmol) and DIEA (8.80 g, 68.1 mmol) in DCM (40.0 mL) was added Tf2O (38.4 g, 136 mmol) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford the title compound (6.4 g, 64.0%) as a brown oil. LCMS m / z = 441 [M+H]+Preparation 98 – 4-cyano-1-phenyl-6,7-dihydro-5H-cyclopenta[c]pyridin-3-yl trifluoromethanesulfonate To a stirred solution of 4-cyano-6,7-dihydro-5H-cyclopenta[c]pyridine-1,3-diyl bis(trifluoromethanesulfonate) (5.00 g, 11.3 mmol) and phenyl boronic acid (692 mg, 5.67 mmol,) in 1,4-dioxane (30.0 mL) and H2O (10.0 mL) were added Pd(dppf)Cl2 (830 mg, 1.13 mmol) and K3PO4 (4.82 g, 22.7 mmol). The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was filtered through a short pad of Celite. The pad was washed with CH2Cl2 (2 × 20 mL). The combined filtrate was concentrated under reduced pressure. The resulting mixture was diluted with water (200 mL) and extracted with CH2Cl2 (3 × 200 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (9:1) to afford the title compound (1.50 g, 35.9%) as a white solid. LCMS m / z = 369 [M+H]+Preparation 99 – N-(4-cyano-1-phenyl-6,7-dihydro-5H-cyclopenta[c]pyridin-3-yl)cyanamide To a mixture of 4-cyano-1-phenyl-6,7-dihydro-5H-cyclopenta[c]pyridin-3-yl trifluoromethanesulfonate (1.35 g, 3.66 mmol) and cyanamide (360 mg, 8.56 mmol) in dioxane (23.0 mL) were added Brettphos Pd G3 (332 mg, 0.367 mmol), Brettphos (197 mg, 0.367 mmol,) and Cs2CO3 (2.39 g, 7.33 mmol). The resulting mixture was stirred at 100 °C undernitrogen atmosphere for 1 h. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered through a short pad of Celite. The pad was washed with MeOH (3 × 20 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLCBto afford the title compound (340 mg, 35.6%) as a brown solid. LCMS m / z = 261 [M+H]+Preparation 100 – N3-(3-morpholinopropyl)-6-phenyl-8,9-dihydro-7H- cyclopenta[4,5]pyrido[2,3-d]pyrimidine-1,3-diamine To a stirred solution of N-(4-cyano-1-phenyl-6,7-dihydro-5H-cyclopenta[c]pyridin-3- yl)cyanamide (150 mg, 0.576 mmol) in EtOH (7.50 mL) was added 4-morpholinepropanamine (220 µL, 1.52 mmol). The resulting mixture was stirred at 100 °C for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLCBto afford the title compound (36.1 mg, 15.5%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 7.85 – 7.68 (m, 2H), 7.65 – 7.37 (m, 3H), 6.75 (br, 2H), 6.57 (br, 1H), 3.58 (t, J = 4.6 Hz, 4H), 3.39 – 3.31 (m, 4H), 3.01 (t, J = 7.4 Hz, 2H), 2.40 – 2.27 (m, 6H), 2.14 – 2.02 (m, 2H), 1.77 – 1.60 (m, 2H). LCMSCm / z = 405 [M+H]+Example 130: 6-chloro-5,7-dimethyl-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine- 2,4-diamine.A solution of Example 5 (100 mg, 0.349 mmol) and 1-chloropyrrolidine-2,5-dione (93.3 mg, 0.698 mmol) in THF (1.0 mL) and MeOH (1.0 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in water (5 mL) and extracted with EtOAc (3 × 10 mL). The combined organic phase was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLCANto afford the title compound (48.2 mg, 45.2%) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 6.88 (br, 2H), 6.55 (br, 1H), 3.83 - 3.68 (m, 1H), 2.80 - 2.69 (m, 5H), 2.53 (s, 3H), 2.16 (s, 3H), 2.00 - 1.87 (m, 2H), 1.86 - 1.74 (m, 2H), 1.59 - 1.44 (m, 2H). LCMSCm / z = 321 [M+H]+. Example 131: tert-butyl 4-((4-amino-5,7-dimethylpyrido[2,3-d]pyrimidin-2- yl)amino)azepane-1-carboxylateTo a stirred mixture of 2-chloro-5,7-dimethylpyrido[2,3-d]pyrimidin-4-amine (60 mg, 0.288 mmol) in 1,4-dioxane (2 mL) at room temperature was added tert-butyl 4-aminoazepane-1- carboxylate (92.45 mg, 0.432 mmol) and CsF (130.46 mg, 0.864 mmol). The resulting mixture was stirred for 16 h at 110 °C. The solution was cooled to room temperature and purified by Agela MP-Flash200Libraryto afford the title compound as a solid (50 mg, 44.90 %). LCMSLibraryA: m / z = 387 [M+H]+. Example 132 – Example 139 The following Examples were synthesised in a similar manner to that described for Example 131, using the appropriate amine reagent: E E E . EE E E E EExample 140: N2-(azepan-4-yl)-5,7-dimethylpyrido[2,3-d]pyrimidine-2,4-diamineTo a stirred mixture of Example 131 (50 mg, 0.129 mmol) in DCM (2 mL) at room temperature was added 4.0 M HCl in 1,4-dioxane (0.5 mL). The resulting mixture was stirred for 2 h at room temperature. Removed the solvent under pressure to afford the title compound as a solid hydrochloride salt (22.8 mg, 54.88%). LCMSLibrary E: m / z = 287 [M+H]+.Example 141: 5,7-dimethyl-N2-(piperidin-4-ylmethyl)pyrido[2,3-d]pyrimidine-2,4- diamineSynthesized in a similar manner to that described for Example 140, from Example 133. LCMS Library B: m / z = 287 [M+H]+. Example 142: N2-(2-(dimethylamino)ethyl)-5,7-dimethylpyrido[2,3-d]pyrimidine-2,4- diamineTo a stirred mixture of 2-chloro-5,7-dimethylpyrido[2,3-d]pyrimidin-4-amine (50 mg, 0.240 mmol) in 1,4-Dioxane (2 mL) at room temperature was added N1,N1-dimethylethane-1,2- diamine (31.73 mg, 0.360 mmol) and CsF (108.72 mg, 0.72mmol). The resulting mixture was stirred for 16 h at 110 °C. The solution was cooled to room temperature and purified by Agela MP-Flash200Libraryto afford the title compound as a solid (24.7mg, 39.58%). LCMSLibrary A: m / z = 261 [M+H]+. Example 143 – Example 218 The following Examples were synthesised in a similar manner to that described for Example 142, using the appropriate amine reagent: E EE E E E E EE E E E E E EE E E E E E E EE I: E E E E E E E EE E E E E E E EE E E E E E E E EE E E E E E E E I: EE I: E E E I: E E E E I: EE E E E E I: E E E EE +Example 219: N2-(1-((dimethylamino)methyl)cyclopropyl)-5,7-dimethylpyrido[2,3- d]pyrimidine-2,4-diamine To a stirred mixture of 2-chloro-5,7-dimethylpyrido[2,3-d]pyrimidin-4-amine (60 mg, 0.29 mmol) in ethyl alcohol (1 mL) at room temperature was added 1- ((dimethylamino)methyl)cyclopropan-1-amine (98.7 mg, 0.86 mmol). The solvent was removed under reduced pressure and then the resulting neat mixture was stirred for 6-12 h at 110 °C. The solution was cooled to room temperature and purified by Agela MP-Flash200Libraryto afford the title compound as a solid (3.7 mg, 4.5%). LCMSLibrary B: m / z = 287 [M+H]+. Example 220 – Example 222 The following Examples were synthesised in a similar manner to that described for Example 219, using the appropriate amine reagent: E E EEExample 223: (R)-N2-(1-(2-methoxyethyl)pyrrolidin-3-yl)-5,7-dimethylpyrido[2,3- d]pyrimidine-2,4-diaminePreparation 101 – tert-butyl (R)-(1-(2-methoxyethyl)pyrrolidin-3-yl)carbamate To a stirred solution of tert-butyl (R)-pyrrolidin-3-ylcarbamate (500 mg, 2.68 mmol) and 1- bromo-2-methoxyethane (448 mg, 3.22 mmol) in ACN (75.0 mL) were added K2CO3(1.86 g, 13.4 mmol) and KI (446 mg, 2.68 mmol) at room temperature. The resulting mixture was stirred at 80 °C overnight. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with ACN (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA : MeOH = 10 : 1) to afford the title compound as a yellow oil (520 mg, 79.3%). LCMS m / z = 245 [M+H]+Preparation 102 – (R)-1-(2-methoxyethyl)pyrrolidin-3-amine hydrogen chloride A mixture of tert-butyl (R)-(1-(2-methoxyethyl)pyrrolidin-3-yl)carbamate (520 mg, 2.13 mmol) and 4.0 M HCl in 1,4-dioxane (4.0 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. This resulted in the title compound as a yellow oil (470 mg, crude). LCMS m / z = 145 [M+H]+Preparation 103 – (R)-N2-(1-(2-methoxyethyl)pyrrolidin-3-yl)-5,7-dimethylpyrido[2,3- d]pyrimidine-2,4-diamine To a stirred solution of (R)-1-(2-methoxyethyl)pyrrolidin-3-amine hydrogen chloride (458 mg, 2.54 mmol) and 2-chloro-5,7-dimethylpyrido[2,3-d]pyrimidin-4-amine (230 mg, 1.10 mmol) in dioxane (8.00 mL) was added Et3N (919 uL, 6.61 mmol) at room temperature. The resulting mixture was stirred at 100 °C overnight. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLCAVto afford the title compound as a yellow solid (170 mg, 16.2%, ee>99%).1H NMR (400 MHz, Methanol-d4) δ 6.79 (s, 1H), 4.67 - 4.57 (m, 1H), 3.53 (t, J = 5.6Hz, 2H), 3.34 (s, 3H), 3.01 - 2.80 (m, 2H), 2.75 - 2.67 (m, 5H), 2.65 - 2.52 (m, 2H), 2.50 - 2.43 (m, 3H), 2.39 - 2.29 (m, 1H), 1.80 - 1.62 (m, 1H). LCMSRm / z = 317 [M+H]+Example 224: (R)-2-(3-((4-amino-5,7-dimethylpyrido[2,3-d]pyrimidin-2- yl)amino)pyrrolidin-1-yl)ethan-1-olA mixture of Example 223 (145 mg, 0.458 mmol) and 1 M BBr3 in DCM (3.0 mL) was stirred at room temperature for 1 h. The reaction was quenched with water / ice at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLCVto afford the title compound as a white solid (27.9 mg, 20.1%, ee>99%).1H NMR (400 MHz, Methanol-d4) δ 6.80 (s, 1H), 4.68 - 4.55 (m, 1H), 3.68 (t, J = 6.1 Hz, 2H), 3.05 - 2.83 (m, 2H), 2.71 (s, 3H), 2.69 - 2.52 (m, 4H), 2.47 (s, 3H), 2.41 - 2.30 (m, 1H), 1.78 - 1.65 (m, 1H). LCMSSm / z = 303 [M+H]+Example 225: (R)-5,7-dimethyl-N2-(piperidin-3-yl)pyrido[2,3-d]pyrimidine-2,4-diaminePreparation 104 – tert-butyl (R)-3-((4-amino-5,7-dimethylpyrido[2,3-d]pyrimidin-2- yl)amino)piperidine-1-carboxylate A mixture of 2-chloro-5,7-dimethylpyrido[2,3-d]pyrimidin-4-amine (300 mg, 1.43 mmol) and tert-butyl (R)-3-aminopiperidine-1-carboxylate (345 mg, 1.72 mmol) in DMSO (5.00 mL) was stirred at 120 °C overnight. The mixture was allowed to cool down to room temperature. The residue was purified by Prep-HPLCAWto afford the title compound as a yellow oil (340 mg, 63.4%). LCMS m / z = 373 [M+H]+. Preparation 105 – (R)-5,7-dimethyl-N2-(piperidin-3-yl)pyrido[2,3-d]pyrimidine-2,4-diamine A mixture of tert-butyl (R)-3-((4-amino-5,7-dimethylpyrido[2,3-d]pyrimidin-2- yl)amino)piperidine-1-carboxylate (340 mg, 0.913 mmol) and HCl in dioxane (5.00 M, 4.0 M) was stirred at room temperature for 20 min. The resulting mixture was concentrated under reduced pressure. The residue was diluted with MeOH and basified to pH 7 with NH3·H2O. The residue was purified by Prep-HPLCLto afford the title compound asa white solid (24.2 mg, 9.70%, ee>99%).1H NMR (400 MHz, DMSO-d6) δ 6.89 - 6.55 (m, 3H), 6.25 (s, 1H), 3.91 - 3.79 (m, 1H), 3.23 - 3.11 (m, 1H), 3.00 (d, J = 11.4 Hz, 1H), 2.76 (d, J = 12.4 Hz, 1H), 2.63 (s, 3H), 2.48 - 2.30 (m, 5H), 1.89 - 1.74 (m, 1H), 1.69 - 1.55 (m, 1H), 1.49 - 1.33 (m, 2H). LCMSSm / z = 273 [M+H]+. Example 226: (3S,4S)-4-((4-amino-5,7-dimethylpyrido[2,3-d]pyrimidin-2-yl)amino)-1- methylpyrrolidin-3-olPreparation 106 – tert-butyl (3S,4S)-3-((4-amino-5,7-dimethylpyrido[2,3-d]pyrimidin-2- yl)amino)-4-hydroxypyrrolidine-1-carboxylate To a stirred solution of 2-chloro-5,7-dimethylpyrido[2,3-d]pyrimidin-4-amine (1.00 g, 4.79 mmol) in dioxane (15.0 mL) at room temperature was added tert-butyl (3S,4S)-3-amino-4- hydroxypyrrolidine-1-carboxylate (1.94 g, 9.60 mmol, 2.00 equiv). The resulting mixture was stirred at 60 °C for 4 h. The mixture was allowed to cool down to room temperature. The precipitated solids were collected by filtration and washed with EtOAc (3 x 10 mL). This resulted in the title compound as an off-white solid (1.40 g, crude). LCMS m / z = 375 [M+H]+. Preparation 107 – (3S,4S)-4-((4-amino-5,7-dimethylpyrido[2,3-d]pyrimidin-2-yl)amino)-1- methylpyrrolidin-3-ol To a stirred solution of tert-butyl (3S,4S)-3-((4-amino-5,7-dimethylpyrido[2,3-d]pyrimidin-2- ylamino)-4-hydroxypyrrolidine-1-carboxylate (1.00 g, 2.67 mmol) in THF (25 mL) was added 1 M LiAlH4 in THF (21.4 mL) dropwise at 0 °C. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with methanol at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLCASto afford the title compound as a white solid (54.1 mg, 6.7%, ee>99%).1H NMR (400 MHz, DMSO-d6) δ 6.96 - 6.78 (m, 3H), 6.75 (s, 1H), 6.02 (s, 1H), 4.08 - 3.82 (m, 2H), 2.85 (t, J = 8.3 Hz, 1H), 2.76 - 2.68 (m, 1H), 2.66 (s, 3H), 2.48 - 2.40 (m, 2H), 2.39 (s, 3H), 2.21 (s, 3H). LCMSTm / z = 289 [M+H]+. Example 227: N2-((3S,4S)-4-methoxypyrrolidin-3-yl)-N4,5,7-trimethylpyrido[2,3- d]pyrimidine-2,4-diaminePreparation 108 – 2-chloro-N,5,7-trimethylpyrido[2,3-d]pyrimidin-4-amine To a stirred mixture of 2,4-dichloro-5,7-dimethylpyrido[2,3-d]pyrimidine (3.00 g, 13.2 mmol) and Et3N (2.66 g, 26.3 mmol) in THF (60.0 mL) was added methanamine hydrochloride (1.72 g, 26.3 mmol) in portions at 0 °C. The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was diluted with water (100 mL). The precipitated solids were collected by filtration and washed with water (3 x 10 mL). This result in the title compound (1.60 g, 54.6%) as a pink solid. LCMS m / z = 223 [M+H]+. Preparation 109 – tert-butyl (3S,4S)-3-((5,7-dimethyl-4-(methylamino)pyrido[2,3-d]pyrimidin- 2-yl)amino)-4-methoxypyrrolidine-1-carboxylate To a solution of 2-chloro-N,5,7-trimethylpyrido[2,3-d]pyrimidin-4-amine (200 mg, 0.89 mmol) in 1,4-dioxane (2.00 mL) was added tert-butyl (3S,4S)-3-amino-4-methoxypyrrolidine-1- carboxylate (233 mg, 1.07 mmol). The resulting mixture was stirred at 100 °C overnight. Then, the resulting mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by Prep-HPLCAVto afford the title compound (362 mg, crude) as an off-white solid. LCMS m / z = 403 [M+H]+. Preparation 110 – N2-((3S,4S)-4-methoxypyrrolidin-3-yl)-N4,5,7-trimethylpyrido[2,3- d]pyrimidine-2,4-diamine To a solution of tert-butyl (3S,4S)-3-([5,7-dimethyl-4-(methylamino)pyrido[2,3-d]pyrimidin-2- yl]amino-4-methoxypyrrolidine-1-carboxylate (340 mg, 0.840 mmol) in 1,4-dioxane (3.40 mL) was added 4 M HCl in MeOH (3.00 mL). The resulting mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was dissolved in MeOH (2.00 mL) and basified to pH 9 with Et3N. The residue was purified by Prep-HPLCAVto afford the title compound (130.8 mg, 50.3%, ee>99%) as an off-white solid.1H NMR (400 MHz, DMSO - d6) δ 6.96 - 6.72 (m, 2H), 6.69 (s, 1H), 4.36 - 4.25 (m, 1H), 3.76 - 3.71 (m, 1H), 3.32 (s, 3H), 3.12 - 3.00 (m, 2H), 2.95 (s, 3H), 2.71 - 2.62 (m, 5H), 2.38 (s, 3H). LCMSUm / z = 303 [M+H]+. Example 228: N2-((3S,4S)-4-methoxy-1-methylpyrrolidin-3-yl)-N4,5,7- trimethylpyrido[2,3-d]pyrimidine-2,4-diamineA solution of Example 227 (95.0 mg, 0.314 mmol) in DCM (1.00 mL) was treated with paraformaldehyde (47.1 mg, 1.57 mmol) for 30 min at room temperature followed by the addition of STAB (532 mg, 2.51 mmol) in portions at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by the addition of water (2 mL). The solid was filtered out, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLCAVto afford the title compound (21.7 mg, 21.0%, ee>99%) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 6.95 - 6.59 (m, 3H), 4.40 - 4.274 (m, 1H), 3.89 - 3.77 (m, 1H), 3.25 (s, 3H), 3.00 - 2.83 (m, 4H), 2.73 - 2.59 (m, 4H), 2.49 - 2.43 (m, 1H), 2.37 (s, 3H), 2.27 - 2.16 (m, 4H). LCMSUm / z = 317 [M+H]+. Example 229: N2-(1-benzylpiperidin-4-yl)-5-methyl-7,8-dihydro-6H- cyclopenta[5,6]pyrido[2,3-d]pyrimidine-2,4-diamineTo a stirred mixture of N-(3-cyano-4-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2- yl)cyanamide (100 mg, 0.504 mmol) in EtOH (5.0 mL) at room temperature was added 1- benzylpiperidin-4-amine (192 mg, 1.01 mmol). The resulting mixture was stirred at 100 °C for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLCLto afford the title compound as a white solid (24.7 mg, 12.6%).1H NMR (300 MHz, DMSO-d6) δ 7.38 - 7.19 (m, 5H), 6.64 (s, 2H),6.30 (s, 1 H), 3.89 - 3.70 (m, 1H), 3.46 (s, 2H), 2.94 - 2.73 (m, 6H), 2.57 (s, 3H), 2.10 - 1.93 (m, 4H), 1.87 - 1.73 (m, 2H), 1.57 - 1.39 (m, 2H). LCMSVm / z = 389 [M+H]+. Example 230: (R)-5-methyl-N2-(pyrrolidin-3-yl)-7,8-dihydro-6H- cyclopenta[5,6]pyrido[2,3-d]pyrimidine-2,4-diaminePreparation 111 – mixture of ethyl 3-amino-1-methyl-6,7-dihydro-5H-cyclopenta[c]pyridine-4- carboxylate and ethyl 2-amino-4-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylateTo a stirred mixture of ethyl 2-carbamimidoylacetate hydrochloride (66.0 g, 396 mmol) and piperidine (101 g, 1190 mmol) in EtOH (1.00 L) at room temperature was added acetylcyclopentanone (50.0 g, 396 mmol) dropwise. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was diluted with PE (100 mL). The precipitated solids were collected by filtration and purified by silica gel column with ethyl acetate / petroleum ether (3:1) to afford ethyl 3-amino- 1-methyl-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carboxylate (35.0 g, 40.1%) as white solid. The filtrate was concentrated under reduced pressure. The residue was purified by Prep- HPLCAWto afford ethyl 2-amino-4-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate (21.0 g, 24.0%) as off-white solid. LCMS m / z = 221 [M+H]+. Preparation 112 – ethyl 4-methyl-2-(3-(2,2,2-trichloroacetyl)ureido)-6,7-dihydro-5H- cyclopenta[b]pyridine-3-carboxylate To a stirred solution of ethyl 2-amino-4-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3- carboxylate (21.0 g, 95.0 mmol) in THF (210 mL) was added trichloroethanecarbonyl isocyanate (26.8 g, 142 mmol) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column with ethyl acetate / petroleum ether (3:1) to afford the title compound as white solid (38.0 g, 98.0%). LCMS m / z = 408 [M+H]+. Preparation 113 – 5-methyl-7,8-dihydro-6H-cyclopenta[5,6]pyrido[2,3-d]pyrimidine-2,4-diol Into a pressure tank reactor were added ethyl 1-methyl-3-(3-(2,2,2-trichloroacetyl)ureido)-6,7- dihydro-5H-cyclopenta[c]pyridine-4-carboxylate (38.0 g, 93.1 mmol) and 7.0 M NH3 in MeOH (70.0 mL) in EtOH (460 mL) at room temperature. The resulting mixture was stirred at 80 °C overnight. The mixture was allowed to cool down to 0 °C. The precipitated solids were collected by filtration and washed with EtOH (3 × 20 mL). This resulted in the title compound (19.2 g, 95.0%) as white solid. LCMS m / z = 218 [M+H]+. Preparation 114 – 2,4-dichloro-5-methyl-7,8-dihydro-6H-cyclopenta[5,6]pyrido[2,3- d]pyrimidine To a stirred mixture of 5-methyl-7,8-dihydro-6H-cyclopenta[5,6]pyrido[2,3-d]pyrimidine-2,4- diol (5.0 g, 2.30 mmol) and DIEA (20.0 mL, 11.5 mmol) in ACN (90.0 mL) was added POCl3 (21.5 mL, 23.0 mmol,) dropwise at 0 °C. The resulting mixture was stirred at 60 °C for 2 h. The mixture was allowed to cool down to room temperature. To the above mixture was added 4 M HCl in 1,4-dioxane (25.0 mL) dropwise over 30 min at 0 °C. The resulting mixture was stirred at room temperature for additional 2 h. The resulting mixture was concentrated under reduced pressure. The reaction was quenched by the addition of sat. NaHCO3 (aq.) at 0 °C.The resulting mixture was extracted with DCM (3 × 100 mL). The combined organic layers were washed with brine (1 ×100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound (3.8 g, crude). The crude product was used in the next step directly without further purification. LCMS m / z = 254 [M+H]+. Preparation 115 – 2-chloro-5-methyl-7,8-dihydro-6H-cyclopenta[5,6]pyrido[2,3-d]pyrimidin-4- amine A mixture of 2,4-dichloro-5-methyl-7,8-dihydro-6H-cyclopenta[5,6]pyrido[2,3-d]pyrimidine (3.00 g, 11.8 mmol, 1.00 eq.) and NH3.H2O (60.0 mL) was stirred at room temperature for 2 days. The precipitated solids were collected by filtration and washed with water (3 × 30 mL). The solids were purified by trituration with ethyl acetate (30 mL). This resulted in the title compound (1.30 g, crude) as a black solid. LCMS m / z = 235 [M+H]+. Preparation 116 – tert-butyl (R)-3-((4-amino-5-methyl-7,8-dihydro-6H- cyclopenta[5,6]pyrido[2,3-d]pyrimidin-2-yl)amino)pyrrolidine-1-carboxylate A mixture of 2-chloro-5-methyl-7,8-dihydro-6H-cyclopenta[5,6]pyrido[2,3-d]pyrimidin-4-amine (900 mg, 3.84 mmol) and tert-butyl (R)-3-aminopyrrolidine-1-carboxylate (2.86 g, 15.3 mmol) in dioxane (9.00 mL) was stirred at 100 °C overnight. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The crude product (800 mg) as brown yellow was used in the next step directly without further purification. LCMS m / z = 385 [M+H]+. Preparation 117 – (R)-5-methyl-N2-(pyrrolidin-3-yl)-7,8-dihydro-6H-cyclopenta[5,6]pyrido[2,3- d]pyrimidine-2,4-diamine A mixture of tert-butyl (R)-3-((4-amino-5-methyl-7,8-dihydro-6H-cyclopenta[5,6]pyrido[2,3- d]pyrimidin-2-yl)amino)pyrrolidine-1-carboxylate (800 mg, 2.08 mmol) and 4.0 M HCl in 1,4- dioxane (8.00 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure and diluted with MeOH (8.00 mL). The residue was basified to pH 9 with TEA. The residue was purified by Prep-HPLCAVto afford the title compound (377.8 mg, 63.8%, ee>99%) as light orange solid.1H NMR (400 MHz, DMSO-d6) δ 6.90 - 6.32 (m, 3H), 4.44 - 4.27 (m, 1H), 2.98 - 2.79 (m, 6H), 2.79 - 2.69 (m, 1H), 2.64 (dd, J = 11.2, 4.6 Hz, 1H), 2.58 (s, 3H), 2.14 - 1.92 (m, 3H), 1.68 - 1.54 (m, 1H). LCMSWm / z = 285 [M+H]+. Example 231: (R)-N4,5-dimethyl-N2-(pyrrolidin-3-yl)-7,8-dihydro-6H- cyclopenta[5,6]pyrido[2,3-d]pyrimidine-2,4-diaminePreparation 118 – 2-chloro-N,5-dimethyl-7,8-dihydro-6H-cyclopenta[5,6]pyrido[2,3- d]pyrimidin-4-amine A mixture of 2,4-dichloro-5-methyl-7,8-dihydro-6H-cyclopenta[5,6]pyrido[2,3-d]pyrimidine (1.00 g, crude) and methylamine (2.0 M in THF, 10.0 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLCAVto afford the title compound as brown solid (210 mg, 18.5% for two steps). LCMS m / z = 249 [M+H]+. Preparation 119 – tert-butyl (R)-3-((5-methyl-4-(methylamino)-7,8-dihydro-6H- cyclopenta[5,6]pyrido[2,3-d]pyrimidin-2-yl)amino)pyrrolidine-1-carboxylate A mixture of 2-chloro-N,5-dimethyl-7,8-dihydro-6H-cyclopenta[5,6]pyrido[2,3-d]pyrimidin-4- amine (300 mg, 1.20 mmol) and tert-butyl (R)-3-aminopyrrolidine-1-carboxylate (447 mg, 2.40 mmol) in 1,4-dioxane (6.0 mL) was stirred at 100 °C for 1 h. The mixture was allowed to cool down to room temperature. The residue was purified by Prep-HPLCBto afford the title compound (200 mg, 41.6%) as yellow oil. LCMS m / z = 399 [M+H]+. Preparation 120 – (R)-N4,5-dimethyl-N2-(pyrrolidin-3-yl)-7,8-dihydro-6H- cyclopenta[5,6]pyrido[2,3-d]pyrimidine-2,4-diamine A mixture of tert-butyl (R)-3-((5-methyl-4-(methylamino)-7,8-dihydro-6H- cyclopenta[5,6]pyrido[2,3-d]pyrimidin-2-yl)amino)pyrrolidine-1-carboxylate (200 mg, 0.502 mmol) and 4.0 M HCl in 1,4-dioxane (4.00 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. Then it was diluted with MeOH (2.00 mL) and basified to pH 9 with NH3·H2O. The residue was purified by Prep-HPLCAVto afford the title compound (115.9 mg, 77.4%, ee>99%) as yellow solid.1H NMR (400 MHz, DMSO-d6) δ 6.93 - 6.64 (m, 2H), 4.46 -4.30 (m, 1H), 3.65 - 3.50 (m, 1H), 3.15 - 3.02 (m, 2H), 2.94 (d, J = 4.1 Hz, 3H), 2.92 - 2.76 (m, 5H), 2.59 (s, 3H), 2.11 - 1.96 (m, 3H), 1.84 - 1.69 (m, 1H). LCMSWm / z = 299 [M+H]+. Example 232: (3S,4S)-1-methyl-4-((5-methyl-4-(methylamino)-7,8-dihydro-6H- cyclopenta[5,6]pyrido[2,3-d]pyrimidin-2-yl)amino)pyrrolidin-3-olPreparation 121 – tert-butyl (3S,4S)-3-hydroxy-4-((5-methyl-4-(methylamino)-7,8-dihydro-6H- cyclopenta[5,6]pyrido[2,3-d]pyrimidin-2-yl)amino)pyrrolidine-1-carboxylate To a stirred solution of 2-chloro-N,5-dimethyl-7,8-dihydro-6H-cyclopenta[5,6]pyrido[2,3- d]pyrimidin-4-amine (1.50 g, 6.03 mmol) in dioxane (10.0 mL) at room temperature was added tert-butyl (3S,4S)-3-amino-4-hydroxypyrrolidine-1-carboxylate (1.95 g, 9.65 mmol). The resulting mixture was stirred at 100 °C overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLCAWto afford the title compound as a yellow solid (950 mg, 38.0%). LCMS m / z = 415 [M+H]+. Preparation 122 – (3S,4S)-4-((5-methyl-4-(methylamino)-7,8-dihydro-6H- cyclopenta[5,6]pyrido[2,3-d]pyrimidin-2-yl)amino)pyrrolidin-3-ol To a stirred solution of tert-butyl (3S,4S)-3-hydroxy-4-((5-methyl-4-(methylamino)-7,8- dihydro-6H-cyclopenta[5,6]pyrido[2,3-d]pyrimidin-2-yl)amino)pyrrolidine-1-carboxylate (450 mg, 1.09 mmol) in dioxane (3.0 mL) at room temperature was added HCl in 1,4-dioxane (7.0 mL, 4.0 M). The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was concentrated under reduced pressure to afford the title compound as a light yellow solid (300 mg, crude). Preparation 123 – (3S,4S)-1-methyl-4-((5-methyl-4-(methylamino)-7,8-dihydro-6H- cyclopenta[5,6]pyrido[2,3-d]pyrimidin-2-yl)amino)pyrrolidin-3-ol To a stirred solution of (3S,4S)-4-((5-methyl-4-(methylamino)-7,8-dihydro-6H- cyclopenta[5,6]pyrido[2,3-d]pyrimidin-2-yl)amino)pyrrolidin-3-ol (300 mg, 0.954 mmol) and Et3N (265 uL, 1.91 mmol) in DCM (6.0 mL) at room temperature was added paraformaldehyde (516 mg, 5.72 mmol). The resulting mixture was stirred at room temperature for 40 min. To the above mixture at room temperature was added STAB (1.21 g, 5.72 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was quenched by the addition of water (15 mL) at room temperature. The resulting mixture was filtered, the filter cake was washed with water (1 x 10 mL). The filtrate was concentrated under reduced pressure. The mixture was basified to pH 9 with Et3N. The residue was purified by Prep-HPLCMto afford the title compound as a yellow solid (145 mg, 46.3%).1H NMR (400 MHz, Methanol-d4) δ 4.33 – 4.12 (m, 2H), 3.18 - 3.00 (m, 4H), 3.03 - 2.88 (m, 5H), 2.64 (s, 3H), 2.60 - 2.49 (m, 2H), 2.37 (s, 3H), 2.13 (p, J = 7.6 Hz, 2H). LCMSRm / z = 329 [M+H]+.Example 233: N2-((3S,4R)-4-fluoro-1-methylpyrrolidin-3-yl)-N4,5-dimethyl-7,8-dihydro- 6H-cyclopenta[5,6]pyrido[2,3-d]pyrimidine-2,4-diaminePreparation 124 – tert-butyl (3R,4S)-3-fluoro-4-((5-methyl-4-(methylamino)-7,8-dihydro-6H- cyclopenta[5,6]pyrido[2,3-d]pyrimidin-2-yl)amino)pyrrolidine-1-carboxylate Into a 100 mL round-bottom flask were added 2-chloro-N,5-dimethyl-7,8-dihydro-6H- cyclopenta[5,6]pyrido[2,3-d]pyrimidin-4-amine (1.00 g, 4.03 mmol) and tert-butyl (3S,4R)-3- amino-4-fluoropyrrolidine-1-carboxylate (987 mg, 4.84 mmol) in dioxane (20.0 mL) at room temperature. The resulting mixture was stirred at 100 °C for 5 h. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (12:1) to afford title compound (600 mg, 35.8%) as brown solid. LCMS m / z = 417 [M+H]+. Preparation 125 – N2-((3S,4R)-4-fluoro-1-methylpyrrolidin-3-yl)-N4,5-dimethyl-7,8-dihydro- 6H-cyclopenta[5,6]pyrido[2,3-d]pyrimidine-2,4-diamine A mixture of tert-butyl (3R,4S)-3-fluoro-4-((5-methyl-4-(methylamino)-7,8-dihydro-6H- cyclopenta[5,6]pyrido[2,3-d]pyrimidin-2-yl)amino)pyrrolidine-1-carboxylate (270 mg, 0.648 mmol) and 37% wt formaldehyde solution (0.270 mL) in formic acid (2.70 mL) was stirred at 100 °C for 1 h. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The resulting mixture was diluted with MeOH (4.00 mL) and basified to pH 9 with TEA. The residue was purified by Prep-HPLCAXto afford the title compound (87.4 mg, 40.9%, ee>98%) as light orange solid.1H NMR (400 MHz, DMSO-d6) δ 6.99 - 6.33 (m, 2H), 5.15 (d, J = 55.9 Hz, 1H), 4.61 - 4.44 (m, 1H), 3.24 - 3.10 (m, 1H), 3.02 - 2.82 (m, 8H), 2.69 - 2.63 (m, 1H), 2.60 (s, 3H), 2.57 - 2.54 (m, 1H), 2.31 (s, 3H), 2.03 (p, J = 7.6 Hz, 2H).19F NMR (376 MHz, DMSO-d6) δ -187.85. LCMSUm / z = 331 [M+H]+. Example 234: (R)-N4-ethyl-5-methyl-N2-(1-methylpyrrolidin-3-yl)-7,8-dihydro-6H- cyclopenta[5,6]pyrido[2,3-d]pyrimidine-2,4-diaminePreparation 126 – 2-chloro-N-ethyl-5-methyl-7,8-dihydro-6H-cyclopenta[5,6]pyrido[2,3- d]pyrimidin-4-amine To a stirred mixture of 2,4-dichloro-5-methyl-7,8-dihydro-6H-cyclopenta[5,6]pyrido[2,3- d]pyrimidine (1.00 g, 3.94 mmol) in THF (20 mL) was added ethylamine (950 mL, 9.84 mmol, 70% wt. in H2O). The resulting mixture was stirred at room temperature for 1 h. The precipitated solids were collected by filtration and washed with water (3 × 10 mL). This resulted in the title compound (600 mg, crude) as brown yellow solid which was used in the next step directly without further purification. LCMS m / z = 263 [M+H]+. Preparation 127 – (R)-N4-ethyl-5-methyl-N2-(1-methylpyrrolidin-3-yl)-7,8-dihydro-6H- cyclopenta[5,6]pyrido[2,3-d]pyrimidine-2,4-diamine A mixture of 2-chloro-N-ethyl-5-methyl-7,8-dihydro-6H-cyclopenta[5,6]pyrido[2,3-d]pyrimidin- 4-amine (300 mg, 1.14 mmol) and (R)-1-methylpyrrolidin-3-amine (229 mg, 2.28 mmol) in 1,4- dioxane (3.00 mL) was stirred at 100 °C overnight. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by Prep-HPLCANto afford the title compound (18.2 mg, 4.88%, ee>99%) as pink solid.1H NMR (400 MHz, Methanol-d4) δ 4.68 - 4.56 (m, 1H), 3.61 (q, J = 7.0 Hz, 2H), 3.06 - 2.90 (m, 5H), 2.87 - 2.71 (m, 1H), 2.70 - 2.52 (m, 5H), 2.46 - 2.33 (m, 4H), 2.13 (p, J = 7.7 Hz, 2H), 1.86 - 1.73 (m, 1H), 1.29 (t, J = 7.1 Hz, 3H). LCMSOm / z = 327 [M+H]+. Example 235: methyl 4-amino-2-((1-methylpiperidin-4-yl)amino)pyrido[2,3- d]pyrimidine-7-carboxylateTo a stirred solution of 7-chloro-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4- diamine (1.00 g, 3.42 mmol) in MeOH (100 mL) and DMF (2.00 mL) were added Pd(dppf)Cl2(250 mg, 0.342 mmol,) and Et3N (691 mg, 6.83 mmol) at room temperature. The resulting mixture was stirred under carbon monoxide atmosphere at 100 °C overnight. The resulting mixture was allowed to cool down to room temperature and filtered, the filter cake was washed with MeOH (3 × 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by trituration with EtOAc (30 mL). This resulted in the title compound (1.64 g, crude) as an orange solid.1H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 8.2 Hz, 1H), 7.80 - 7.30 (m, 3H), 6.88 (d, J = 7.2 Hz, 1H), 3.98 - 3.80 (m, 4H), 2.97 - 2.85 (m, 2H), 2.34 - 2.04 (m, 5H), 1.98 - 1.78 (m, 2H), 1.66 - 1.49 (m, 2H). LCMS m / z = 317 [M+H]+Example 236: 4-amino-2-((1-methylpiperidin-4-yl)amino)pyrido[2,3-d]pyrimidine-7- carboxylic acidTo a stirred solution of methyl 4-amino-2-((1-methylpiperidin-4-yl)amino)pyrido[2,3- d]pyrimidine-7-carboxylate (50.0 mg, 0.158 mmol) in THF (500 μL) and H2O (500 μL) were added LiOH.H2O (66.3 mg, 1.58 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h, then it was acidified to pH 5 with 1.0 M HCl (aq.). The resulting mixture was filtered, the filter cake was washed with water (3 × 2 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLCAVto afford the title compound (25.1 mg, 79.6% over two steps) as a white solid.1H NMR (400 MHz, DMSO- d6) δ 8.41 (d, J = 8.1 Hz, 1H), 7.74 - 7.27 (m, 3H), 6.63 (d, J = 8.3 Hz, 1H), 4.01 - 3.78 (m, 1H), 2.81 - 2.66 (m, 2H), 2.16 (s, 3H), 1.92 (t, J = 11.7, 2H), 1.85 - 1.70 (m, 2H), 1.65 - 1.45 (m, 2H). LCMSXm / z = 303 [M+H]+Example 237: 7-(methoxymethyl)-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine- 2,4-diamineTo a stirred solution of Example 23 (100 mg, 0.342 mmol) and tributyl(methoxymethyl)stannane (229 mg, 0.684 mmol) in NMP (3.00 mL) was added Pd(PPh3)4 (39.5 mg, 0.030 mmol) at room temperature. The resulting mixture was stirred under nitrogen atmosphere at 130 °C for 2 h. The mixture was allowed to cool down to room temperature and purified by Prep-HPLCAVto afford the title compound as a light yellow solid (3.0 mg, 2.90%).1H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J = 8.2 Hz, 1H), 7.71 - 7.17 (br, 2H), 7.03 (d, J = 8.1 Hz, 1H), 6.70 - 6.49 (br, 1H), 4.46 (s, 2H), 3.89 - 3.71 (m, 1H), 3.38 (s, 3H), 2.80 - 2.68 (m, 2H), 2.16 (s, 3H), 2.01 - 1.89 (m, 2H), 1.85 - 1.76 (m, 2H), 1.58 - 1.42 (m, 2H). LCMSYm / z = 303 [M+H]+. Example 238: N2-(1-methylpiperidin-4-yl)-7-(prop-1-en-2-yl) pyrido[2,3-d]pyrimidine-2,4- diamineTo a stirred solution of Example 23 (300 mg, 1.03 mmol) in dioxane (5.00 mL) and H2O (1.00 mL) was added prop-1-en-2-ylboronic acid (123 mg, 1.54 mmol), Pd(dppf)Cl2(75.0 mg, 0.100 mmol) and K3PO4(435 mg, 2.04 mmol). The resulting mixture was stirred under nitrogen atmosphere at 100 °C for 1 h. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by Prep-HPLCAVto afford the title compound as a white solid (190 mg, 62.0%).1H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J = 8.1 Hz, 1H), 7.79 - 7.08 (m, 3H), 6.88 - 6.37 (m, 1H), 5.96 (s, 1H), 5.42 (s, 1H), 3.98 - 3.70 (m, 1H), 2.76 (d, J = 11.1 Hz, 2H), 2.18 (s, 3H), 2.16 (s, 3H), 2.08 - 1.88 (m, 2H), 1.88 - 1.71 (m, 2H), 1.62 - 1.42 (m, 2H). LCMS m / z = 299 [M+H]+. Example 239: 7-isopropyl-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4- diamineA mixture of Example 238 (50.0 mg, 0.168 mmol) and Pd / C (25.0 mg,10% wt) in MeOH (3.00 mL) was stirred at room temperature under hydrogen atmosphere for 1 h. The mixture was filtered through a short pad of Celite, the filter cake was washed with MeOH (3 × 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLCAUto afford the title compound as a white solid (11.1 mg, 22.0%).1H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J = 8.2 Hz, 1H), 7.28 (s, 2H), 6.92 (d, J = 8.2 Hz, 1H), 6.47 (s, 1H), 3.91 - 3.73 (m, 1H), 3.07 - 2.90 (m, 1H), 2.74 (d, J = 11.1 Hz, 2H), 2.16 (s, 3H), 1.96 (t, J = 11.5 Hz, 2H), 1.86 - 1.73 (m, 2H), 1.57 - 1.43 (m, 2H), 1.23 (d, J = 6.9 Hz, 6H). LCMSZm / z = 301 [M+H]+. Example 240: 2-(4-amino-2-((1-methylpiperidin-4-yl)amino)pyrido[2,3-d]pyrimidin-7- yl)propan-1-olPreparation 128 – 2-(4-amino-2-((1-methylpiperidin-4-yl)amino)pyrido[2,3-d]pyrimidin-7- yl)propan-1-ol To a stirred solution of Example 238 (90.0 mg, 0.302 mmol) in THF (0.50 mL) was added 9- borabicyclo[3.3.1]nonane (2.11 mL, 1.05 mmol, 0.5 M in THF) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. To the above mixture was added second batches of 9- borabicyclo[3.3.1]nonane (1.2 mL, 0.60 mmol) at 0°C. The mixture was stirred for 1 hours at room temperature and then followed by addition of third batches of 9- borabicyclo[3.3.1]nonane (1.2 mL, 0.60 mmol) 0 °C. The resulting mixture was stirred at room temperature overnight. The reaction mixture was cooled to 0 °C and added 30% H2O2(1.03 g, 9.06 mmol) and 1M aq. NaOH (0.45 mL) at 0 °C. The resulting mixture was stirred for additional 2 h at room temperature. The reaction was quenched by the addition of Na2SO3(10 mL) at 0 °C，then it was concentrated under reduced pressure. The residue was purified by Prep-HPLCAVto afford the title compound (7.60 mg, 8.0%).1H NMR (400 MHz, DMSO-d6) δ 8.24 (d, J = 8.2 Hz, 1H), 7.33 (br, 2H), 6.91 (d, J = 8.2 Hz, 1H), 6.48 (s, 1H), 4.85 - 4.56 (m, 1H), 3.93 - 3.75 (m, 1H), 3.73 - 3.63 (m, 1H), 3.60 - 3.50 (m, 1H), 3.00 - 2.87 (m, 1H), 2.79 (d, J = 11.2 Hz, 2H), 2.20 (s, 3H), 2.11 - 1.97 (m, 2H), 1.87 - 1.77 (m, 2H), 1.62 - 1.45 (m, 2H), 1.20 (d, J = 6.9 Hz, 3H). LCMSWm / z = 317 [M+H]+. Example 241: 6-methoxy-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4- diamineTo a stirred mixture of Example 20 (200 mg, 0.593 mmol) and Pd(PPh3)4(68.5 mg, 0.060 mmol) in methanol (2.00 mL) and dioxane (2.00 mL) were added di-tert-butyl((2-[2,4,6- tris(propan-2-yl)phenyl]phenyl)phosphane (25.2 mg, 0.060 mmol) and Cs2CO3(387 mg, 1.19 mmol) at room temperature. The resulting mixture was stirred under nitrogen atmosphere at 100 °C for 6 h. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLCNto afford the title compound as a yellow solid (5.6 mg, 3.25%).1H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J = 3.0 Hz, 1H), 7.93 (d, J = 3.2 Hz, 1H), 7.34 (s, 2H), 6.35 (s, 1H), 3.81 (s, 3H), 3.78 – 3.70 (m, 1H), 2.74 (d, J = 11.4 Hz, 2H), 2.16 (s, 3H), 2.00 - 1.89 (m, 2H), 1.86 - 1.76 (m, 2H), 1.56 - 1.42 (m, 2H). LCMSZm / z = 289 [M+H]+.Example 242: 6-(methoxymethyl)-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine- 2,4-diaminePreparation 129 – 6-(chloromethyl)-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4- diamine A mixture of Example 123 (50.0 mg, 0.173 mmol) in SOCl2 (1.00 mL) was stirred at 80 °C for 1 h . The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. This resulted in the title compound (50 mg, crude) as a black solid which was used in the next step directly without further purification. LCMS m / z: 307 [M+H]+Preparation 130 – 6-(methoxymethyl)-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4- diamine A mixture of 6-(chloromethyl)-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamine (50.0 mg, 0.163 mmol) and NaOMe in MeOH (30% wt, 1.50 mL) was stirred at 0 °C for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLCLto afford product (38 mg, crude) as a yellow solid. The crude product was further purified by Prep-HPLCAUto afford the title compound (2.6 mg, 5.3%) as an oyster white solid.1H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 2.3 Hz, 1H), 8.33 (d, J = 2.4 Hz, 1H), 7.40 (br, 2H), 6.58 (br, 1H), 4.40 (s, 2H), 3.85 – 3.73 (m, 1H), 3.29 (s, 3H), 2.74 (d, J = 11.1 Hz, 2H), 2.16 (s, 3H), 1.94 (t, J = 11.7 Hz, 2H), 1.81 (d, J = 12.3 Hz, 2H), 1.59 – 1.39 (m, 2H). LCMSVm / z: 303 [M+H]+Example 243: 6-cyclopentyl-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4- diamineA mixture of nickel acetylacetonate (7.62 mg, 0.030 mmol),([4,4′-Bis(1,1-dimethylethyl)-2,2′- bipyridine-N1,N1′]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]Iridium(III) hexafluorophosphate (3.33 mg, 0.003 mmol) and 4-tert-butyl-2-(4-tert-butylpyridin-2- yl)pyridine (7.96 mg, 0.030 mmol), MgCl2(28.2 mg, 0.297 mmol) in DMF (4.00 mL) was stirred under nitrogen atmosphere at room temperature for 5 min. Then to the above mixture wasadded a mixture of Example 20 (100 mg, 0.297 mmol), bromocyclopentane (221 mg, 1.49 mmol) and Et3N (124 μL, 0.891 mmol) in DMF (4.00 mL). The resulting mixture was under nitrogen atmosphere at room temperature stirred for 5 h under blue LEDs. The solution was purified by Prep-HPLCLto afford the title compound as a light red solid (53.0 mg, crude). The crude product was further purified by Prep-HPLCAYto afford the title compound as an off- white solid (17.6 mg, 18.2%).1H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 2.4 Hz, 1H), 8.23 (d, J = 2.5 Hz, 1H), 7.38 (s, 2H), 6.44 (s, 1H), 3.84 - 3.69 (m, 1H), 3.04 - 2.94 (m, 1H), 2.74 (d, J = 11.4 Hz, 2H), 2.16 (s, 3H), 2.09 - 1.99 (m, 2H), 1.98 - 1.89 (m, 2H), 1.86 - 1.74 (m, 4H), 1.72 - 1.61 (m, 2H), 1.60 - 1.43 (m, 4H). LCMSAAm / z = 327 [M+H]+. Example 244: 4-amino-2-((1-methylpiperidin-4-yl)amino)pyrido[2,3-d]pyrimidin-5-olPreparation 131 – N-(3-cyano-4-methoxypyridin-2-yl)cyanamide To a stirred mixture of 2-chloro-4-methoxypyridine-3-carbonitrile (3.75 g, 22.2 mmol) and K2CO3(6.15 g, 44.5 mmol) in dioxane (40.0 mL) at room temperature were added BrettPhos (2.39 g, 4.45 mmol), cyanamide (1.88 g, 44.5 mmol) and BrettPhos Pd G3(4.03 g, 4.45 mmol). The resulting mixture was stirred under nitrogen atmosphere at 60oC for 1 h. The resulting mixture was filtered, the filter cake was washed with MeOH (5 × 100 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was diluted with water (200 mL) and was acidified to pH 5 with 1 M HCl. The precipitated solids were collected by filtration and washed with water (3 × 100 mL) to afford the title compound as a white solid (3.20 g, 82.6%). LCMS m / z = 175 [M+H]+. Preparation 132 – 5-methoxy-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamine A mixture of 2-(cyanoamino)-4-methoxypyridine-3-carbonitrile (3.20 g, 18.4 mmol) and 1- methylpiperidin-4-amine (4.20 g, 36.8 mmol) in dioxane (60.0 mL) was stirred at 120 °C overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with EtOAc (200 mL) to afford the title compound as a yellow solid (2.48 g, 46.8%). LCMS m / z = 289 [M+H]+. Preparation 133 – 4-amino-2-((1-methylpiperidin-4-yl)amino)pyrido[2,3-d]pyrimidin-5-ol Into a 100 mL round-bottom flask were added 5-methoxy-N2-(1-methylpiperidin-4- yl)pyrido[2,3-d]pyrimidine-2,4-diamine (2.38 g, 8.25 mmol) and aq. HCl (25.0 mL, 6.0 M ) at room temperature. The resulting mixture was stirred at 100 °C for 2 h. The resultingmixture was concentrated under reduced pressure to afford the title compound as a yellow solid (3.00 g, crude).1H NMR (400 MHz, DMSO-d6) δ 11.41 - 10.83 (m, 1H), 9.52 - 9.13 (m, 1H), 7.59 - 7.00 (m, 2H), 6.78 (d, J = 8.2 Hz, 1H), 5.80 (d, J = 7.6 Hz, 1H), 3.81 - 3.63 (m, 1H), 2.73 (d, J = 11.1 Hz, 2H), 2.12 (s, 3H), 1.88 (t, J = 13.2, 2H), 1.76 (d, J = 12.2 Hz, 2H), 1.56 - 1.28 (m, 2H). LCMS m / z = 275 [M+H]+. Example 245: N2-(1-methylpiperidin-4-yl)-5-(prop-1-en-2-yl)pyrido[2,3-d]pyrimidine-2,4- diaminePreparation 134 – 5-chloro-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamine Into a 100 mL round-bottom flask were added 4-amino-2-[(1-methylpiperidin-4- yl)amino]pyrido[2,3-d]pyrimidin-5-ol (2.50 g, 9.11 mmol) and POCl3 (30.0 mL) at room temperature. The resulting mixture was stirred at 80oC for 1 h. The resulting mixture was concentrated under reduced pressure. The reaction was quenched with Water / Ice at 0oC. The mixture was basified to pH 8 with saturated NaHCO3 (aq.). The aqueous layer was extracted with CH2Cl2 / MeOH (10:1, 3 × 100 mL) to afford the title compound as a yellow solid (1.05 g, 39.4%). LCMS m / z = 293 [M+H]+. Preparation 135 – N2-(1-methylpiperidin-4-yl)-5-(prop-1-en-2-yl)pyrido[2,3-d]pyrimidine-2,4- diamine To a stirred mixture of 5-chloro-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamine (150 mg, 0.512 mmol) and K3PO4 (285 mg, 1.34 mmol) in dioxane (5.00 mL) and H2O (1.00 mL) were added Pd(dppf)Cl2 (45.0 mg, 0.0610 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2- yl)-1,3,2-dioxaborolane (225 uL, 1.21 mmol) at room temperature. The resulting mixture was stirred at 100oC under nitrogen atmosphere for 1 h. The resulting mixture was filtered, the filter cake was washed with MeOH (2 x 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLCAVto afford the title compound as a white solid (100 mg, 65.4%).1H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 4.5 Hz, 1H), 7.34 - 6.20 (m, 4H), 5.43(s, 1H), 5.15 (s, 1H), 3.87 - 3.70 (m, 1H), 2.79 - 2.64 (m, 2H), 2.16 (s, 3H), 2.09 (s, 3H), 1.94 (t, J = 11.5 Hz, 2H), 1.87 - 1.69 (m, 2H), 1.64 - 1.42 (m, 2H). LCMS m / z = 299 [M+H]+. Example 246: 5-isopropyl-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4- diamineA mixture of Example 245 (40.0 mg, 0.135 mmol) and 10% Pd / C (40 mg) in EA (16.0 mL) was stirred at room temperature under hydrogen atmosphere for 8 h. The resulting mixture was filtered, the filter cake was washed with MeOH (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified silica gel column chromatography, eluted with CH2Cl2 / MeOH / Et3N (10:1:0.06) to afford the title compound as a white solid (17.5 mg, 43.4%).1H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J = 4.9 Hz, 1H), 7.91 - 7.25 (m, 1H), 7.14 - 6.52 (m, 3H), 4.12 - 3.93 (m, 1H), 3.85 - 3.69 (m, 1H), 3.08 - 2.81 (m, 2H), 2.67 (s, 3H), 2.13 - 1.97(m, 2H), 1.92 - 1.69 (m, 2H), 1.34 - 1.08 (m, 7H), 0.98 - 0.73 (m, 1H). LCMSEm / z = 301 [M+H]+. Example 247: N5-methyl-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4,5- triaminePreparation 136 – N5-(4-methoxybenzyl)-N5-methyl-N2-(1-methylpiperidin-4-yl)pyrido[2,3- d]pyrimidine-2,4,5-triamine A mixture of 5-chloro-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamine (150 mg, 0.512 mmol) and 1-(4-methoxyphenyl)-N-methylmethanamine (2.00 mL) was stirred at 100 °C for 1 h. The mixture was allowed to cool down to room temperature and was purified by Prep- HPLCAVto afford the title compound (150 mg, 71.8%) as a yellow solid. LCMS m / z = 408 [M+H]+. Preparation 137 – N5-methyl-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4,5-triamine A solution of N5-(4-methoxybenzyl)-N5-methyl-N2-(1-methylpiperidin-4-yl)pyrido[2,3- d]pyrimidine-2,4,5-triamine (150 mg, 0.368 mmol) in TFA (2.00 mL) was stirred at 100 °C for 1 h. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was basified to pH 9 with NH3·H2O. The residue was purified by Prep-HPLCAVto afford the title compound (44.0 mg, 41.6%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.07 - 9.69 (m, 2H), 7.47 - 6.45 (m, 2H), 6.27 (s, 1H), 5.95 (s, 1H), 3.76 -3.59 (m, 1H), 2.89 (s, 3H), 2.72 (d, J = 11.1 Hz, 2H), 2.14 (s, 3H), 1.90 (t, J = 11.6 Hz, 2H), 1.77 (d, J = 11.8 Hz, 2H), 1.55 - 1.39 (m, 2H). LCMSABm / z = 288 [M+H]+. Example 248: 5-(methoxymethyl)-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine- 2,4-diamineTo a stirred mixture of 5-chloro-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4- diamine (70.0 mg, 0.239 mmol) and tributyl(methoxymethyl)stannane (160 mg, 0.478 mmol) in NMP (8.00 mL) was added Pd(PPh3)2Cl2(16.7 mg, 0.0240 mmol) and 4 Å MS (140 mg). The resulting mixture was stirred under nitrogen atmosphere at 120 °C for 4 h. The resulting mixture was allowed to cool down to room temperature, then was diluted with saturated KF (aq.) (20 mL). The resulting mixture was extracted with CH2Cl2(3 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLCAVto afford the title compound as a brown solid (6.5 mg, 8.99%).1H NMR (400 MHz, Methanol-d4) δ 8.64 - 8.51 (m, 1H), 7.03 (d, J = 4.7 Hz, 1H), 4.71 (s, 2H), 4.04 - 3.93 (m, 1H), 3.45 (s, 3H), 2.88 (d, J = 11.8 Hz, 2H), 2.31 (s, 3H), 2.28 - 2.19 (m, 2H), 2.09 - 2.01 (m, 2H), 1.68 - 1.54 (m, 2H). LCMSACm / z = 303 [M+H]+. Example 249: 5-ethynyl-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamineTo a stirred mixture of 5-chloro-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamine (200 mg, 0.683 mmol) and CuI (13.0 mg, 0.0680 mmol) in DMF (4.0 mL) were added Pd(dppf)Cl2 (50.0 mg, 0.0680 mmol) and Et3N (346 mg, 3.415 mmol). To the above mixture was added trimethylsilylacetylene (335 mg, 3.42 mmol) at room temperature. The resulting mixture was stirred under nitrogen atmosphere at 80 °C for 3 h. The mixture was allowed to cool down to room temperature and was filtered, the filter cake was washed with MeOH (3 × 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLCAVto afford the title compound as a white solid as an off-white solid (3.2 mg,1.62%).1H NMR (400 MHz, DMSO-d6) δ 8.21 - 7.56 (m, 2H), 6.89 (d, J = 7.8 Hz, 1H), 6.55 (s, 2H), 3.93 - 3.73 (m, 1H), 3.05 - 2.81 (m, 2H), 2.41 - 2.19 (m, 4H), 1.91 (d, J = 12.8 Hz, 2H), 1.67 - 1.53 (m, 2H), 1.27 - 1.16 (m, 2H). LCMSADm / z = 283 [M+H]+. Example 250: 4-amino-2-((1-methylpiperidin-4-yl)amino)pyrido[2,3-d]pyrimidine-5- carbonitrileTo a stirred solution of 5-chloro-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4- diamine (80.0 mg, 0.273 mmol) in NMP (2.00 mL) were added Zn(CN)2(64.1 mg, 0.546 mmol), Zn (35.7 mg, 0.546 mmol), Pd2(dba)3(25.0 mg, 0.0270 mmol) and dppf (15.0 mg, 0.0270 mmol). The resulting mixture was stirred under nitrogen atmosphere at 100 °C for 1 h. The resulting mixture was filtered, the filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLCAXto afford the title compound as a light yellow solid (21.0 mg, 27.1%).1H NMR (400 MHz, DMSO- d6) δ 8.78 (d, J = 4.5 Hz, 1H), 7.57 - 7.30 (m, 2H), 7.27 - 7.02 (m, 2H), 3.86 - 3.70 (m, 1H), 2.75 (d, J = 11.1 Hz, 2H), 2.16 (s, 3H), 1.94 (t, J = 11.6 Hz, 2H), 1.80 (d, J = 12.2 Hz, 2H), 1.61 - 1.46 (m, 2H). LCMSAEm / z = 284 [M+H]+. Example 251: N2-(1-methylpiperidin-4-yl)-5-(prop-1-yn-1-yl)pyrido[2,3-d]pyrimidine-2,4- diamineTo a stirred mixture of 5-chloro-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamine (100 mg, 0.342 mmol) and Pd(dppf)Cl2 (25.0 mg, 0.034 mmol) in DMF (4.00 mL) was added tributyl(prop-1-yn-1-yl)stannane (562 mg, 1.71 mmol). The mixture was stirred under nitrogen atmosphere at 120 °C for 1 h. The resulting mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by Prep- HPLCAVto afford the title compound (20.1 mg, 19.9%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.41(br, 1 H), 7.52 (br, 1H), 6.65 (s, 1H), 6.40 (s, 2H), 3.86 - 3.72 (m, 1H), 2.76(d, J = 11.4 Hz, 2H), 2.29 (s, 3H), 2.17 (s, 3H), 2.06 - 1.88 (m, 2H), 1.83 (d, J = 12.3 Hz, 2H), 1.59 - 1.44 (m, 2H). LCMSAFm / z = 297 [M+H]+. Example 252: 5-(1-methoxyethyl)-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine- 2,4-diaminePreparation 138 – 5-(1-methoxyvinyl)-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4- diamine To a stirred mixture of 5-chloro-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4- diamine (100 mg, 0.342 mmol) and Pd(PPh3)4(39.5 mg, 0.0340mmol) in NMP (2.00 mL) was added tributyl(1-methoxyethenyl)stannane (237 µL, 0.684 mmol) at room temperature. The resulting mixture was stirred under nitrogen atmosphere at 120 °C for overnight. The reaction was quenched with sat. KF (aq.) at room temperature. The resulting mixture was extracted with CH2Cl2(3 × 50 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH / NH3.H2O (10:1:0.1) to afford the title compound as a brown semi-solid (60.0 mg, 55.8%). LCMS m / z = 315 [M+H]+. Preparation 139 – 5-(1-methoxyethyl)-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4- diamine A solution of 5-(1-methoxyvinyl)-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4- diamine (56.0 mg, 0.178 mmol) and 20% Pd(OH)2 / C (56.0 mg) in MeOH (5.00 mL) was stirred at room temperature under hydrogen atmosphere overnight. The resulting mixture was filtered through a short pad of Celite, the filter cake was washed with MeOH (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLCAVto afford the title compound as an off-white solid (5.6 mg, 9.70%).1H NMR (400 MHz, Methanol-d4) δ 8.58 (d, J = 4.7 Hz, 1H), 7.07 (d, J = 4.7 Hz, 1H), 4.73 (q, J = 6.8 Hz, 1H), 4.16 - 4.03 (m, 1H), 3.36 (s, 3H), 3.25 - 3.10 (m, 2H), 2.80 - 2.63 (m, 2H), 2.59 (s, 3H), 2.23 - 2.11 (m, 2H), 1.81 - 1.68 (m, 2H), 1.58 (d, J = 6.8 Hz, 3H). LCMSYm / z = 317 [M+H]+. Example 253: 5-methyl-N2-(3-morpholinopropyl)-7-(m-tolyl)pyrido[2,3-d]pyrimidine-2,4- diaminePreparation 140 – methyl 2-amino-4,6-dihydroxypyridine-3-carboxylate To a stirred solution of 1,5-dimethyl 3-oxopentanedioate (20.0 g, 115 mmol) and aminoformonitrile (5.79 g, 138 mmol) in DME (200 mL) was added nickel acetylacetonate (150 mg, 0.574 mmol) at room temperature. The resulting mixture was stirred at 80oC overnight. The mixture was allowed to cool down to room temperature. The precipitated solids were collected by filtration and washed with DME (3 × 2 mL). The resulting solids was diluted with MeOH (100 mL) and was stirred for 30 min at room temperature. The precipitated solids were collected by filtration and washed with MeOH (3 × 10 mL). The solid was dried under vacuum. This resulted in the title compound (8.80 g, 41.6%) as a tan solid. LCMS m / z = 185 [M+H]+. Preparation 141 – methyl 2-amino-4,6-dichloronicotinate To a stirred mixture of methyl 2-amino-4,6-dihydroxypyridine-3-carboxylate (3.00 g, 16.3 mmol) in POCl3(45.0 mL) was added DIEA (9.00 mL) at room temperature. The resulting mixture was stirred at 60 °C overnight. The mixture was allowed to cool down to room temperature and concentrated under vacuum. The residue was added to the NaHCO3(aq.) dropwise at 0 °C. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in the title compound (2.0 g, crude) as a brown solid. LCMS m / z = 221 [M+H]+. Preparation 142 – methyl 2-amino-4-chloro-6-(m-tolyl)nicotinate To a stirred mixture of methyl 2-amino-4,6-dichloropyridine-3-carboxylate (2.03 g, 9.18 mmo) and 3-methylphenylboronic acid (1.50 g, 11.0 mmol) in 1,4-dioxane (40.0 mL) and H2O (4.00 mL) at room temperature were added Pd(PPh3)4(1.06 g, 0.918 mmol) and K3PO4(2.92 g, 13.8 mmol). The resulting mixture was stirred under nitrogen atmosphere at 60 °C for 3 h. The mixture was allowed to cool down to room temperature and diluted with H2O (100 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford the title compound (1.38 g, 54.3%) as a yellow solid. LCMS m / z = 277 [M+H]+.Preparation 143 – methyl 2-amino-4-methyl-6-(m-tolyl)nicotinate To a stirred mixture of methyl 2-amino-4-chloro-6-(m-tolyl)nicotinate (1.24 g, 4.48 mmol) and methylboronic acid (805 mg, 13.4 mmol) in 1,4-dioxane (18.0 mL) at room temperature were added Pd(dppf)Cl2.CH2Cl2(365 mg, 0.448 mmol) and K3PO4(2.85 g, 13.4 mmol). The resulting mixture was stirred under nitrogen atmosphere at 110 °C for 1 h. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with H2O (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2:1) to afford the title compound (606 mg, 52.7%) as a yellow solid. LCMS m / z = 257 [M+H]+. Preparation 144 – 5-methyl-7-(m-tolyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione A solution of methyl 2-amino-4-methyl-6-(m-tolyl)nicotinate (576 mg, 2.25 mmol) and 2,2,2- trichloroethanecarbonyl isocyanate (423 mg, 2.25 mmol) in THF (9.00 mL) was stirred under nitrogen atmosphere at room temperature for 30 min. The resulting mixture was concentrated under reduced pressure. To the above mixture was added 7.0 M NH3 in MeOH (9.00 mL) at room temperature. The resulting mixture was stirred for additional 30 min at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with MTBE (20 mL). This resulted in the title compound (570 mg, 94.8%) as a white solid. LCMS m / z = 268 [M+H]+. Preparation 145 – 2,4-dichloro-5-methyl-7-(m-tolyl)pyrido[2,3-d]pyrimidine A mixture of 5-methyl-7-(m-tolyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (500 mg, 1.87 mmol) and DIEA (2.00 mL) in POCl3 (10 mL) was stirred at 100 °C for 1 h. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LCMS m / z = 304 [M+H]+. Preparation 146 – 2-chloro-5-methyl-7-(m-tolyl)pyrido[2,3-d]pyrimidin-4-amine To a stirred mixture of 2,4-dichloro-5-methyl-7-(m-tolyl)pyrido[2,3-d]pyrimidine (300 mg, 0.986 mmol) in ACN (12.0 mL) at 0 °C was added NH3.H2O (3.00 mL) . The resulting mixture was stirred at 0 °C for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (20 mL). The resulting mixture was filtered, the filter cake was washed with MeOH (3 × 2 mL). The filtrate was concentrated under reduced pressure. The residue was dissolved in ACN (20 mL). The solid was filtered out, the filter cake was washedwith ACN (3 x 2 mL). The filtrate was concentrated under reduced pressure. This resulted in the title compound (166 mg, crude) as a brown solid. LCMS m / z = 285 [M+H]+. Preparation 147 – 5-methyl-N2-(3-morpholinopropyl)-7-(m-tolyl)pyrido[2,3-d]pyrimidine-2,4- diamine To a stirred mixture of 2-chloro-5-methyl-7-(m-tolyl)pyrido[2,3-d]pyrimidin-4-amine (70.0 mg, 0.246 mmol) and 4-morpholinepropanamine (70.9 mg, 0.492 mmol) in 1,4-dioxane (4.00 mL) was added CsF (74.7 mg, 0.492 mmol). The resulting mixture was stirred at 100 °C overnight. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by Prep-HPLCAYto afford the title compound as a brown yellow solid (7.2 mg, 7.46%).1H NMR (400 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.50 - 7.21 (m, 2H), 7.29 (d, J = 7.5 Hz, 1H), 6.80 (s, 2H), 6.62 (s, 1H), 3.59 (t, J = 4.6 Hz, 4H), 3.46 - 3.38 (m, 2H), 2.76 (s, 3H), 2.41 (s, 3H), 2.39 - 2.32 (m, 6H), 1.77 - 1.65 (m, 2H). LCMSAEm / z = 393 [M+H]+. Example 254: N2-(4-(dimethylamino)butyl)-5,7-dimethyl-1,8-naphthyridine-2,4-diaminePreparation 148 – ethyl 2-amino-4,6-dimethylnicotinate To a stirred solution of ethyl 3-amino-3-iminopropanoate hydrochloride (10.0 g, 60.0 mmol) in EtOH (90.0 mL) was added piperidine (15.3 g, 180 mmol) and pentane-2,4-dione (9.01 g, 90.0 mmol) dropwise at room temperature. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was diluted with water (300 mL) and extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (2 × 200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10 : 1) to afford the title compound as a light yellow solid (8.0 g, 68.6%). LCMS m / z = 195 [M+H]+. Preparation 149 – 5,7-dimethyl-1,8-naphthyridine-2,4-diol To a stirred solution of ethyl 2-amino-4,6-dimethylnicotinate (6.20 g, 31.9 mmol) in ethyl acetate (200 mL) was added NaH (8.94 g, 223 mmol, 60% in oil) in portions at room temperature. The resulting mixture was stirred at 80 °C for 3 h. The mixture was allowed to cool down to room temperature. The reaction was quenched with Water / Ice at 0 °C and extracted with EtOAc (100 mL × 3). The aqueous layer was acidified to pH 6 with AcOH. The precipitated solids were collected by filtration and washed with water (30 mL × 3). The solidwas dried under vacuum. This resulted in the title compound as an off-white solid (4.8 g, 79.1%). LCMS m / z = 191 [M+H]+Preparation 150 – 2,4-dichloro-5,7-dimethyl-1,8-naphthyridine To a stirred mixture of 5,7-dimethyl-1,8-naphthyridine-2,4-diol (4.30 g, 22.6 mmol) in Toluene (130 mL) was added POCl3(21.1 mL, 226 mmol) and DIEA (11.8 mL, 67.8 mmol) dropwise at 0 °C. The resulting mixture was stirred at 100 °C for 8 h. The mixture was allowed to cool down to room temperature. The resulting mixture was added into saturated NaHCO3(aq.) at 0 °C. The resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (2 × 300 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford the title compound as a red solid (3.7 g, 72.1%). LCMS m / z = 227 [M+H]+. Preparation 151 – 2-chloro-5,7-dimethyl-1,8-naphthyridin-4-amine A solution of 2,4-dichloro-5,7-dimethyl-1,8-naphthyridine (600 mg, 2.64 mmol) and CsF (1.20 g, 7.93 mmol) in NH3.H2O (20.0 mL) and dioxane (20.0 mL) was stirred at 100 °C for 34 h. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLCAVto afford 2- chloro-5,7-dimethyl-1,8-naphthyridin-4-amine as yellow solid (555 mg, crude) and 4-chloro- 5,7-dimethyl-1,8-naphthyridin-2-amine as yellow solid (430 mg, crude, isomer). LCMS m / z = 208 [M+H]+. Preparation 152 – N2-(4-(dimethylamino)butyl)-5,7-dimethyl-1,8-naphthyridine-2,4-diamine To a stirred solution of 2-chloro-5,7-dimethyl-1,8-naphthyridin-4-amine (50.0 mg, 0.240 mmol) and (4-aminobutyl)dimethylamine (280 mg, 2.41 mmol) in dioxane (1.00 mL) were added Cs2CO3 (157 mg, 0.480 mmol) and Pd-PEPPSI-IHeptCl 3-chloropyridine (23.5 mg, 0.020 mmol) at room temperature. The resulting mixture was stirred under nitrogen atmosphere at 100 °C overnight. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (EA / MeOH=1:2) to afford the title compound (1.8 mg, 2.36%).1H NMR (400 MHz, DMSO-d6) δ 6.62 (s, 1H), 6.54 (s, 1H), 5.82 (s, 1H), 5.73 (s, 2H), 3.28 - 3.24(m, 2H), 2.69 (s, 3H), 2.37 (s, 3H), 2.21 (t, J = 6.9 Hz, 2H), 2.11 (s, 6H), 1.58 - 1.41 (m, 4H). LCMSABm / z = 288 [M+H]+. Example 255: (R)-5,7-dimethyl-N2-(pyrrolidin-3-yl)-1,8-naphthyridine-2,4-diaminePreparation 153 – tert-butyl (R)-3-((4-amino-5,7-dimethyl-1,8-naphthyridin-2- yl)amino)pyrrolidine-1-carboxylate To a stirred mixture of 2-chloro-5,7-dimethyl-1,8-naphthyridin-4-amine (500 mg, 2.41 mmol) and tert-butyl (R)-3-aminopyrrolidine-1-carboxylate (897 mg, 4.82 mmol) in dioxane (10.0 mL) were added Cs2CO3(1.57 g, 4.82 mmol) and (SP-4-1)-[1,3-Bis[2,6-bis(1- ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(2- methylpyridine)palladium (203 mg, 0.241 mmol) at room temperature. The resulting mixture was stirred under nitrogen atmosphere at 100 °C for 1 h. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by Prep-HPLCAVto afford the title compound (80.0 mg, 9.29%) as a white solid. LCMS m / z = 358 [M+H]+. Preparation 154 – (R)-5,7-dimethyl-N2-(pyrrolidin-3-yl)-1,8-naphthyridine-2,4-diamine A mixture of tert-butyl (R)-3-((4-amino-5,7-dimethyl-1,8-naphthyridin-2-yl)amino)pyrrolidine-1- carboxylate (75.0 mg, 0.210 mmol) and 4.0 M HCl in 1,4-dioxane (1.00 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure and dissolved in MeOH (1.00 mL). The mixture was basified to pH 9 with NH3·H2O. The residue was purified by Prep-HPLCAVto afford the title compound (22.9 mg, 42.4%, ee>99%) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 8.88 (br, 1H), 6.95 (d, J = 5.9 Hz, 1H), 6.71 (s, 1H), 5.97 (s, 2H), 5.85 (s, 1H), 4.54 - 4.31 (m, 1H), 3.47 - 3.38 (m, 2H), 3.19 - 3.03 (m, 2H), 2.71 (s, 3H), 2.39 (s, 3H), 2.26 - 2.17 (m, 1H), 1.92 - 1.81 (m, 1H). LCMSTm / z = 258 [M+H]+. Example 256: (R)-N4,5,7-trimethyl-N2-(pyrrolidin-3-yl)-1,8-naphthyridine-2,4-diaminePreparation 155 – 2-chloro-N,5,7-trimethyl-1,8-naphthyridin-4-amine To a stirred mixture of 2,4-dichloro-5,7-dimethyl-1,8-naphthyridine (3.00 g, 13.2 mmol) in DMSO (30.0 mL) was added CH3NH2.HCl (1.34 g, 20.0 mmol) and DIEA (3.41 g, 26.4 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 4 h. Theresulting mixture was purified by Prep-HPLCAVto afford the title compound (1.10 g, 37.6%) as a white solid. LCMS m / z = 222 [M+H]+Preparation 156 – tert-butyl (R)-3-((5,7-dimethyl-4-(methylamino)-1,8-naphthyridin-2- yl)amino)pyrrolidine-1-carboxylate A mixture of 2-chloro-N,5,7-trimethyl-1,8-naphthyridin-4-amine (300 mg, 1.35 mmol) and tert- butyl (R)-3-aminopyrrolidine-1-carboxylate (3.00 mL) was stirred at 140 °C for 5 h. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with DMF (5 mL). The residue was purified by Prep-HPLCAVto afford the title compound (408 mg, 81.0%) as a green solid. LCMS m / z = 372 [M+H]+Preparation 157 – (R)-N4,5,7-trimethyl-N2-(pyrrolidin-3-yl)-1,8-naphthyridine-2,4-diamine To a stirred mixture of tert-butyl (R)-3-((5,7-dimethyl-4-(methylamino)-1,8-naphthyridin-2- yl)amino)pyrrolidine-1-carboxylate (390 mg, 1.05 mmol) in 1,4-dioxane (4.00 mL) was added HCl(gas) in 1,4-dioxane (4.00 mL, 4.0 M) dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was dissolved in DMSO (4 mL) and basified to pH 9 with NH3·H2O. The residue was purified by Prep-HPLCAZto afford the title compound (41.1 mg, 11.7%, ee>99%) as a white solid TFA salt.1H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 7.40 - 7.15 (m, 1H), 6.71 (s, 1H), 6.01 - 5.88 (m, 1H), 5.64 (s, 1H), 4.63 - 4.50 (m, 1H), 3.40 - 3.33 (m, 1H), 3.32 -3.24 (m, 1H), 3.20 - 3.11 (m, 1H), 3.07 - 3.00 (m, 1H), 2.76 (d, J = 4.6 Hz, 3H), 2.72 (s, 3H), 2.40 (s, 3H), 2.26 - 2.10 (m, 1H), 1.93 - 1.80 (m, 1H). LCMSAAm / z = 272 [M+H]+Example 257: N4,3,5,7-tetramethyl-N2-(1-methylpiperidin-4-yl)-1,8-naphthyridine-2,4- diaminePreparation 158 – 3,5,7-trimethyl-1,8-naphthyridine-2,4-diol To a stirred solution of ethyl 2-amino-4,6-dimethylnicotinate (14.0 g, 72.2 mmol) and ethyl propionate (174 mL, 1.80 mol) in THF (200 mL) at room temperature was added t-BuOK (48.5 g, 433 mmol). The resulting mixture was stirred at room temperature for 40 min then was stirred at 100 °C for 3 h. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The resulting mixture was diluted with water (150 mL). The residue was basified to pH 7 with HCl (aq.). The precipitated solids were collected byfiltration and washed with water (3 × 10 mL). This affords the title compound as off-white solid (5.70 g, 38.7%). LCMS m / z = 205 [M+H]+. Preparation 159 – 2,4-dichloro-3,5,7-trimethyl-1,8-naphthyridine To a stirred solution of 3,5,7-trimethyl-1,8-naphthyridine-2,4-diol (5.70 g, 27.9 mmol) and DIEA (14.6 mL, 83.7 mmol) in toluene (50.0 mL) at 0 °C was added POCl3(26.0 mL, 279 mmol). The resulting mixture was stirred at 100 °C for 1 h. The mixture was allowed to cool down to room temperature. The reaction was quenched at 0 °C by the addition of sat. NaHCO3(aq.) (300 mL). The mixture was stirred at 0 °C for 15 min. The resulting mixture was extracted with EtOAc (3 × 400 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4. After filtration, the filtrate was concentrated under reduce pressure to afford the title compound as a reddish solid (6.00 g, crude). LCMS m / z = 241 [M+H]+. Preparation 160 – 4-chloro-3,5,7-trimethyl-N-(1-methylpiperidin-4-yl)-1,8-naphthyridin-2- amine To a stirred solution of 2,4-dichloro-3,5,7-trimethyl-1,8-naphthyridine (1.00 g, 4.14 mmol) and 1-methylpiperidin-4-amine (947 mg, 8.29 mmol) in dioxane (10.0 mL) at room temperature was added CsF (189 mg, 12.4 mmol). The resulting mixture was stirred at 100 °C overnight. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by prep-HPLCAVto afford the title compound as white solid (410 mg, 31.0%). LCMS m / z = 319 [M+H]+. Preparation 161 – N4,3,5,7-tetramethyl-N2-(1-methylpiperidin-4-yl)-1,8-naphthyridine-2,4- diamine To a stirred solution of 4-chloro-3,5,7-trimethyl-N-(1-methylpiperidin-4-yl)-1,8-naphthyridin-2- amine (200 mg, 0.648 mmol) and methanamine hydrochloride (105 mg, 1.29 mmol) in dioxane (2.00 mL) was added Pd(OAc)2 (29.0 mg, 0.130 mmol) and Cs2CO3 (422 mg, 1.29 mmol) at room temperature. The resulting mixture was stirred under nitrogen atmosphere at 100 °C for overnight. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by prep-HPLCAUto afford the title compound as yellow solid (27.3 mg, 13.5%).1H NMR (400 MHz, DMSO-d6) δ 6.71 (s, 1H), 5.90 (d, J = 7.8 Hz, 1H), 4.59 (q, J = 5.8 Hz, 1H), 4.14 - 4.02 (m, 1H), 2.84 - 2.75 (m, 2H), 2.74 (s, 3H), 2.66 (d, J = 5.7 Hz, 3H), 2.41 (s, 3H), 2.18 (s, 3H), 2.08 (s, 3H), 2.02 - 1.94 (m, 2H), 1.89 - 1.81 (m, 2H), 1.66 - 1.52 (m, 2H). LCMSAAm / z = 314 [M+H]+. Example 258: (R)-N4,5-dimethyl-N2-(1-methylpyrrolidin-3-yl)-7,8-dihydro-6H- cyclopenta[b][1,8]naphthyridine-2,4-diaminePreparation 162 – 5-methyl-7,8-dihydro-6H-cyclopenta[b][1,8]naphthyridine-2,4-diol To a stirred solution of ethyl 2-amino-4-methyl-5H,6H,7H-cyclopenta[b]pyridine-3-carboxylate (3.50 g, 15.9 mmol) in ethyl acetate (175 mL) was added NaH (4.50 g, 113 mmol, 60%wt in oil) at room temperature. The resulting mixture was stirred at 80 °C for 5 h. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of Water / Ice (200 mL) at 0 °C. The aqueous layer was extracted with EtOAc (3 × 100 mL). The aqueous layer was acidified to pH 6 with AcOH. The precipitated solids were collected by filtration and washed with H2O (3 × 5 mL). The resulting solid was dried under vacuum to afford the title compound as a grey solid (1.50 g, 43.7%). LCMS m / z = 217 [M+H]+Preparation 163 – 2,4-dichloro-5-methyl-7,8-dihydro-6H-cyclopenta[b][1,8]naphthyridine A solution of 5-methyl-6H,7H,8H-cyclopenta[b]1,8-naphthyridine-2,4-diol (1.40 g, 6.47 mmol) in POCl3 (28.0 mL) was stirred at 100 °C for 1 h. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The resulting mixture was diluted with NaHCO3(aq.) (200 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound as a tan solid (1.50 g, crude). LCMS m / z = 253 [M+H]+Preparation 164 – 2-chloro-N,5-dimethyl-7,8-dihydro-6H-cyclopenta[b][1,8]naphthyridin-4- amine To a stirred mixture of 2,4-dichloro-5-methyl-6H,7H,8H-cyclopenta[b]1,8-naphthyridine (1.30 g, 5.14 mmol) and methylamine hydrochloride (413 mg, 6.16 mmol) in DMSO (26.0 mL) was added DIEA (1.33 g, 10.3 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 4 h. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with DMSO (2 × 1 mL). The filtrate was purified by Prep-HPLCLto afford the title compound as a grey solid (540 mg, 42.4%). LCMS m / z = 248 [M+H]+Preparation 165 – (R)-N4,5-dimethyl-N2-(1-methylpyrrolidin-3-yl)-7,8-dihydro-6H- cyclopenta[b][1,8]naphthyridine-2,4-diamine To a stirred solution of 2-chloro-N,5-dimethyl-6H,7H,8H-cyclopenta[b]1,8-naphthyridin-4- amine (100 mg, 0.404 mmol) and (3R)-1-methylpyrrolidin-3-amine (65.0 uL, 0.606mmol) in 1,4-dioxane (2.00 mL) were added Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (6.79 mg, 0.008 mmol) and Cs2CO3(263 mg, 0.808 mmol) at room temperature. The resulting mixture was stirred under nitrogen atmosphere at 100 °C for 3 h. The mixture was allowed to cool down to room temperature and filtered, the filter cake was washed with MeOH (3 × 1 mL). The filtrate was concentrated under reduced pressure. The residue was purified Prep-HPLCLto afford crude product (60 mg). The crude product was further purified by Prep-HPLCAUto afford the title compound as a yellow solid (29.1 mg, 23.2%, ee>99%).1H NMR (400 MHz, Methanol-d4) δ 5.71 (s, 1H), 4.70 - 4.59 (m, 1H), 3.03 - 2.91 (m, 5H), 2.88 (s, 3H), 2.81 - 2.76 (m, 1H), 2.70 (s, 3H), 2.65 - 2.49 (m, 2H), 2.48 - 2.33 (m, 4H), 2.26 - 2.07 (m, 2H), 1.82 - 1.70 (m, 1H). LCMSABm / z = 312 [M+H]+. Example 259: N2-(3-azabicyclo[3.1.0]hexan-1-yl)-5,7-dimethylpyrido[2,3-d]pyrimidine- 2,4-diamine, Isomer 1 Example 260: N2-(3-azabicyclo[3.1.0]hexan-1-yl)-5,7-dimethylpyrido[2,3-d]pyrimidine- 2,4-diamine, Isomer 2Example 259, Isomer 1 Example 260, Isomer 2 Preparation 166 – tert-butyl 1-((4-amino-5,7-dimethylpyrido[2,3-d]pyrimidin-2-yl)amino)-3- azabicyclo[3.1.0]hexane-3-carboxylate A mixture of 2-chloro-5,7-dimethylpyrido[2,3-d]pyrimidin-4-amine (500 mg, 2.40 mmol) and tert-butyl 1-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate (950 mg, 4.79 mmol) in DMSO (8.00 mL) was stirred at 100 °C overnight. The mixture was allowed to cool down to room temperature. The residue was purified by Prep-HPLCAVto afford the title compound as a yellow solid (750 mg, 84.5%). LCMS m / z = 371 [M+H]+. Preparation 167 – N2-((1S,5R)-3-azabicyclo[3.1.0]hexan-1-yl)-5,7-dimethylpyrido[2,3- d]pyrimidine-2,4-diamine and N2-((1R,5S)-3-azabicyclo[3.1.0]hexan-1-yl)-5,7- dimethylpyrido[2,3-d]pyrimidine-2,4-diamine A solution of tert-butyl 1-((4-amino-5,7-dimethylpyrido[2,3-d]pyrimidin-2-yl)amino)-3- azabicyclo[3.1.0]hexane-3-carboxylate( 750 mg, 2.03 mmol) in 4.0 M HCl in 1,4-dioxane (8.0 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure and dissolved in MeOH (1.00 mL). The mixture was basified to pH 9 with NH3·H2O. The residue was purified by Prep-HPLCAVto afford the title compound as a whitesolid (500 mg, 91.3%) and then separated by Chiral-HPLCCto afford Example 259 and Example 260 as off-white solids. The stereochemistry of Example 259 and Example 260 has not been unambiguously confirmed. Example 259, Isomer 1: (51.3 mg, 12.8%, ee>99%, Rt= 9.1 min).1H NMR (400 MHz, DMSO- d6) δ 6.98 (s, 1H), 6.88 - 6.52 (m, 3H), 3.43 - 3.37(m, 1 H), 3.11 (d, J = 10.5 Hz, 2H), 2.88 (d, J = 10.5 Hz, 1H), 2.75 (d, J = 11.0 Hz, 1H), 2.65 (s, 3H), 2.39 (s, 3H), 1.48 (dt, J = 8.4, 4.1 Hz, 1H), 0.92 (t, J = 5.0 Hz, 1H), 0.82 - 0.73 (m, 1H). LCMSTm / z = 271 [M+H]+Example 260, Isomer 2: (44.9 mg, 11.2%, ee>99%, Rt= 14.1 min).1H NMR (400 MHz, DMSO-d6) δ 7.08 - 6.84 (m, 1H), 6.80 - 6.50 (m, 3H), 3.42 - 3.27 (m, 1H), 3.08 (d, J = 10.8 Hz, 2H), 2.80 (d, J = 10.4 Hz, 1H), 2.74 - 2.59 (m, 4H), 2.39 (s, 3H), 1.51 - 1.39 (m, 1H), 0.94 - 0.85 (m, 1H), 0.76 - 0.68 (m, 1H). LCMSTm / z = 271 [M+H]+. Example 261: N4,5,7-trimethyl-N2-(1-methylpiperidin-4-yl)-1,8-naphthyridine-2,4- diaminePreparation 168 – 2-chloro-5,7-dimethyl-N-(1-methylpiperidin-4-yl)-1,8-naphthyridin-4-amine and 4-chloro-5,7-dimethyl-N-(1-methylpiperidin-4-yl)-1,8-naphthyridin-2-amine A solution of 2,4-dichloro-5,7-dimethyl-1,8-naphthyridine (1.00 g, 4.40 mmol) and 1- methylpiperidin-4-amine (1.51 g, 13.2 mmol) in DMSO (10.0 mL) was stirred at 100 °C for 3 h. The mixture was allowed to cool down to room temperature. The residue was purified by HPLCAVto afford the title compound 2-chloro-5,7-dimethyl-N-(1-methylpiperidin-4-yl)-1,8- naphthyridin-4-amine (550 mg, 41.0%) as a yellow solid and 4-chloro-5,7-dimethyl-N-(1- methylpiperidin-4-yl)-1,8-naphthyridin-2-amine (530 mg, 39.5%) as a yellow solid. LCMS m / z = 305 [M+H]+. Preparation 169 – N4,5,7-trimethyl-N2-(1-methylpiperidin-4-yl)-1,8-naphthyridine-2,4-diamine A mixture of 4-chloro-5,7-dimethyl-N-(1-methylpiperidin-4-yl)-1,8-naphthyridin-2-amine (200 mg, 0.656 mmol), methylamine hydrochloride (222 mg, 3.28 mmol), BrettPhos Pd G3 (59.5 mg, 0.066 mmol), BrettPhos (70.4 mg, 0.131 mmol) and Cs2CO3 (278 mg, 2.62 mmol) in DMF (5.00 mL) was stirred under nitrogen atmosphere at 85 °C for 1 h. The mixture was allowed to cool down to room temperature. The residue was purified by HPLCBDto afford the title compound as a white solid (38.9 mg, 19.8%).1H NMR (400 MHz, DMSO-d6) δ 6.62 (s, 1H), 6.53 (d, J = 8.0 Hz, 1H), 5.83 - 5.76 (m, 1H), 5.64 (s, 1H), 3.94 - 3.81 (m, 1H), 2.78 - 2.70 (m,5H), 2.69 (s, 3H), 2.37 (s, 3H), 2.17 (s, 3H), 1.99 (t, J = 11.6 Hz, 2H), 1.90 - 1.81 (m, 2H), 1.49 - 1.36 (m, 2H). LCMSTm / z = 300 [M+H]+. Example 262 – Example 424 These Examples were synthesised according to methods similar to those cited in the following table: E Method 1 LCMS E E 1 E6H).1H NMR (400 MHz, E E E E, , 3H).1H NMR (400 MHz, E E E E E, , . , , 2.37 (s, 3H), 2.16 (s,3H), 1.94 (t, J = 11.5 E E E E. , , . 1.92 (m, 2H), 1.90 -1.69 (m, 2H), 1.62 - E E E E E, . , , . (t, J = 11.8 Hz, 2H),1.86 -1.70 (m, 2H), E E E E, . , . Hz, 3H).1H NMR (400 MHz, E E E E, , . , 6.5 Hz, 3H).1H NMR (400 MHz, E E E E EExample 140 1H).1H NMR (400 MHz, E E E E- 1.44 (m, 2H).1H NMR (400 MHz, E E E E E, amine1H NMR (400 MHz, E E E EHz, 3H).1H NMR (400 MHz, E E E E EExample 140 . , , . 2.01 (m, 1H), 1.88 -1.74 (m, 3H), 1.71 - E E E E, . . , 4H). Formate salt1H NMR (400 MHz, E E E E. , , . 1.41 (m, 2H).1H NMR (400 MHz, E E E E E, . , ., 2.3 Hz, 1H), 2.91 (dd,J = 11.1, 8.7 Hz, 1H), E E E E. , . , . Hz, 2H).Example1H NMR (400 MHz, E E E E E. , , . , 3H), 2.81 (t, J = 10.6Hz, 1H), 2.72 (s, 3H), E E E EHz, 1H).1H NMR (400 MHz, E E E E E. . , , 231, using 3.22 (dd, J = 12.3, 3.7appropriate Hz, 1H), 3.12 - 3.01 E E E E, . , . Hz, 3H).1H NMR (400 MHz, E E E E2H).1H NMR (400 MHz, E E E E. q , . , . Hz, 2H).1H NMR (400 MHz, E E E E E, . , . Hz, 4H), 2.59 (s, 3H),2.31 - 2.19 (m, 5H), E E E Eamne 2.18 (m, 2H).1H NMR (400 MHz, E E E E E. , , . 3.11 (m, 2H), 3.07 (s,3H), 2.84 (dd, J = 11.1, E E E E E, . . , 1H), 2.01 - 1.91 (m,2H), 1.15 (d, J = 6.2 E E E E E, . , . Hz, 3H).1H NMR (400 MHz, E E E E1H).1H NMR (400 MHz, E E E E E. , , . , 3H), 2.20 - 2.05 (m,1H), 1.75 - 1.63 (m, E E E E. . , , 1.29 (t, J = 7.1 Hz, 3H).1H NMR (400 MHz, E E E E- 1.43 (m, 2H).1H NMR (400 MHz, E E E E, . . , 1H).1H NMR (400 MHz, E E E E E. Deprotectionas per E E E E EExample 140Example E E E E EamineExample E E E E 7(m, 1H).1H NMR (400 MHz, E E E E 2Hz, 2H). Example 425: (3S,4S)-1-methyl-4-((5-methyl-4-(methylamino)-7,8-dihydro-6H- cyclopenta[b][1,8]naphthyridin-2-yl)amino)pyrrolidin-3-olPreparation 170 – tert-butyl (3S,4S)-3-hydroxy-4-((5-methyl-4-(methylamino)-7,8-dihydro-6H- cyclopenta[b][1,8]naphthyridin-2-yl)amino)pyrrolidine-1-carboxylate To a stirred mixture of 2-chloro-N,5-dimethyl-7,8-dihydro-6H-cyclopenta[b][1,8]naphthyridin- 4-amine (200 mg, 0.807 mmol) and tert-butyl (3S,4S)-3-amino-4-hydroxypyrrolidine-1- carboxylate (196 mg, 0.968 mmol) in 1,4-dioxane (4.00 mL) were added Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (67.0 mg, 0.081 mmol) and Cs2CO3(526 mg, 1.61 mmol). The resulting mixture was stirred under nitrogen atmosphere at 100 °C for 1 h. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with MeOH (3 × 3.0 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLCAVto afford the title compound as a grey solid (280 mg, 83.9%). LCMS m / z 414 [M+H]+Preparation 171 – (3S,4S)-4-((5-methyl-4-(methylamino)-7,8-dihydro-6H- cyclopenta[b][1,8]naphthyridin-2-yl)amino)pyrrolidin-3-ol A mixture of tert-butyl (3S,4S)-3-hydroxy-4-((5-methyl-4-(methylamino)-7,8-dihydro-6H- cyclopenta[b][1,8]naphthyridin-2-yl)amino)pyrrolidine-1-carboxylate (170 mg, 0.410 mmol) and HCl in 1,4-dioxane (4.00 mL, 4.0 M) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford the title compound (170 mg) as a brown solid, which was used in the next step directly without further purification. LCMS m / z = 314 [M+H]+Preparation 172 – (3S,4S)-1-methyl-4-((5-methyl-4-(methylamino)-7,8-dihydro-6H- cyclopenta[b][1,8]naphthyridin-2-yl)amino)pyrrolidin-3-ol To a stirred mixture of (3S,4S)-4-((5-methyl-4-(methylamino)-7,8-dihydro-6H- cyclopenta[b][1,8]naphthyridin-2-yl)amino)pyrrolidin-3-ol (91.0 mg, 0.290 mmol) and Et3N (118 mg, 1.16 mmol) in DCE (2.00 mL) was added paraformaldehyde (35.0 mg, 1.16 mmol). The mixture was stirred at 40 °C for 3 h. Then to the above mixture was added STAB (246 mg, 1.16 mmol) at room temperature. The resulting mixture was stirred at 40 °C for additional 1 h. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of water / ice (2.0 mL) at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in DCM / MeOH (20.0 mL, 5 / 1). The resulting mixture was filtered, the filter cake was washed with DCM / MeOH (3 × 1.0 mL, 5 / 1). The filtratewas concentrated under reduced pressure. The residue was purified by Prep-HPLCWto afford the title compound as an off-white solid (37.4 mg, 39.4%).1H NMR (400 MHz, DMSO- d6) δ 6.99 (d, J = 3.4 Hz, 1H), 6.72 (s, 1H), 5.95 (q, J = 4.8 Hz, 1H), 5.72 (s, 1H), 3.94 - 3.83 (m, 2H), 2.94 - 2.78 (m, 5H), 2.78 - 2.71 (m, 4H), 2.65 (s, 3H), 2.50 - 2.36 (m, 2H), 2.23 (s, 3H), 2.13 - 1.97 (m, 2H). LCMSAAm / z = 328 [M+H]+Example 426: N2-(1-(2-methoxybenzyl)piperidin-4-yl)-5,7-dimethylpyrido[2,3- d]pyrimidine-2,4-diamineTo a stirred mixture of 5,7-dimethyl-N2-(piperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamine (80 mg, 0.294 mmol, 1 equiv), 2-methoxybenzaldehyde (43.99 mg, 0.323 mmol, 1.1 equiv), acetic acid (0.059 mmol, 0.2 equiv) and sodium triacetoxyborohydride (124.51 mg, 0.588 mmol, 2 equiv) in DMAc (3 mL). The mixture was stirred at 0 °C for 10 min, then heated to 60 °C for 1 hour. The reaction was quenched with MeOH (0.5 mL) at 0 °C and the residue after evaporation was purified by Prep-HPLC to afford the desired product (15.6 mg). LCMS m / z LibraryC= 393 [M+H]+. Example 427: 2-((4-((4-amino-5,7-dimethylpyrido[2,3-d]pyrimidin-2-yl)amino)piperidin- 1-yl)methyl)phenolPreparation 173 – 5,7-dimethylpyrido[2,3-d]pyrimidine-2,4-diol To a stirred mixture of 6-aminouracil (50.0 g, 393 mmol) in acetylacetone (200 mL) at room temperature was added PPA (90.5 g, 786 mmol). The resulting mixture was stirred at 100 °C for 1 h. The mixture was allowed to cool down to room temperature. The reaction was quenched with NaHCO3(aq) at 0 °C. The precipitated solids were collected by filtration and washed with water (2 × 300 mL). The solid was further purified by trituration with MtBE (300 mL). This resulted in title compound as an off-white solid (38.0 g, crude). LCMS m / z = 192 [M+H]+Preparation 174 – 2,4-dichloro-5,7-dimethylpyrido[2,3-d]pyrimidineTo a stirred mixture of 5,7-dimethylpyrido[2,3-d]pyrimidine-2,4-diol (37.5 g, 196 mmol) in POCl3(375 mL) at 0 °C was added N,N-diethylaniline (146 g, 980 mmol) dropwise. The resulting mixture was stirred at 60 °C for 3 h. The resulting mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The mixture basified to pH 8 with saturated NaHCO3(aq.). The resulting mixture was extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4.After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2:1) to afford the title compound as a yellow solid (20.9 g, 46.9%). LCMS: m / z = 228 [M+H]+Preparation 175 – 2-chloro-5,7-dimethylpyrido[2,3-d]pyrimidin-4-amine A mixture of 2,4-dichloro-5,7-dimethylpyrido[2,3-d]pyrimidine (77.5 g, 341 mmol) in ammonium hydroxide (1.00 L) was stirred at room temperature for 3 h. The precipitated solids were collected by filtration and washed with water (3 × 200 mL). The solid was dried under reduced pressure to afford the title compound (65.9 g, crude) as an orange solid. LCMS m / z = 209 [M+H]+. Preparation 176 – 2- tert-butyl 4-((4-amino-5,7-dimethylpyrido[2,3-d]pyrimidin-2- yl)amino)piperidine-1-carboxylate A mixture of 2-chloro-5,7-dimethylpyrido[2,3-d]pyrimidin-4-amine (65.9 g, 317 mmol) and tert- butyl 4-aminopiperidine-1-carboxylate (127 g, 634 mmol) in DMSO (500 mL) was stirred at 100 °C overnight. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (1.50 L) and extracted with DCM (3 × 500 mL). The combined organic layers were washed with brine (3 × 500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with MTBE (2 × 500 mL) to afford the title compound (106 g, 92.9%) as a pink solid. LCMS m / z = 373 [M+H]+Preparation 177 – 5,7-dimethyl-N2-(piperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamine A mixture of tert-butyl 4-((4-amino-5,7-dimethylpyrido[2,3-d]pyrimidin-2-yl)amino)piperidine-1- carboxylate (17.5 g, 47.0 mmol, 1.00 equiv) in 4 M HCl in 1,4-dioxane) (250 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with EtOAc (200 mL). This resulted in the title compound as an off-white solid (12.0 g, crude). LCMS m / z = 273 [M+H]+Preparation 178 – 2-((4-((4-amino-5,7-dimethylpyrido[2,3-d]pyrimidin-2-yl)amino)piperidin-1- yl)methyl)phenolA mixture of 5,7-dimethyl-N2-(piperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamine (600 mg, 2.20 mmol) and 2-hydroxybenzaldehyde (538 mg, 4.40 mmol) in 1,2-dichloroethane (12.0 mL) was stirred at 40 °C for 3 h. To the above mixture was added STAB (1.86 g, 8.81 mmol) at room temperature. The resulting mixture was stirred at 40 °C for additional 0.5 h. The mixture was allowed to cool down to room temperature. The reaction was quenched with Water / Ice at 0 °C. The resulting mixture was filtered, the filter cake was washed with MeOH (5 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep- HPLCAWto afford the title compound as a white solid (382.3 mg, 46.0%).1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 7.14 - 7.04 (m, 2H), 6.88 - 6.38 (m, 6H), 3.96 - 3.83 (m, 1H), 3.66 (s, 2H), 2.90 (d, J = 11.5 Hz, 2H), 2.63 (...

Claims

CLAIMS 1. A compound of formula (I), or a tautomeric form thereof, or a pharmaceutically acceptable salt or N-oxide thereof: I) whereinX is N or CR6; R1is independently selected from C0-C6-alkylene-R1a, and C2-C6-alkylene-R1b; R1ais independently selected from C3-C8cycloalkyl, C5-C8cycloalkenyl, 3- to 10-membered heterocycloalkyl, and 5- to 10-membered heterocycloalkenyl; wherein R1ais optionally substituted with C0-C6-alkylene-R9aand / or from 1 to 6 R9groups; wherein where R1ais heterocycloalkyl or heterocycloalkenyl, the heterocycloalkyl or heterocycloalkenyl is optionally fused to a phenyl ring, wherein the phenyl ring is optionally substituted with from 1 to 4 R10groups; R1bis independently selected from NR7aR8aand OR7; wherein R1comprises at least one nitrogen atom; R2ais independently at each occurrence selected from H and C1-C4alkyl; R2bis independently at each occurrence selected from H, C1-C4alkyl, C1-C4-haloalkyl, C0-C4 alkyl-R2c, C2-C4-alkylene-R2d, C(O)-C1-C4-alkyl, S(O)-C1-C4-alkyl, and S(O)2-C1-C4-alkyl; R2cis independently selected from C3-C8cycloalkyl, C5-C8 cycloalkenyl, phenyl, 3- to 8- membered heterocycloalkyl, 5- to 8-membered heterocycloalkenyl and 5-, or 6-membered heteroaryl; wherein where R2cis cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, R2cis optionally substituted with from 1 to 4 R9groups; and where R2cis phenyl, or heteroaryl, R2cis optionally substituted with from 1 to 5 R10groups; R2dis independently selected from NR7R8and OR7;R3is independently selected from H, cyano, C1-C4-alkylene-NR7R8, NR7R8, C1-C4-alkylene- OR7, OR7, SR7, SOR7, S(O)2R7, S(O)2NR7R7, CO2R7, C(O)R7, C(O)NR7R7, C1-C4-alkyl, C2- C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, NR7-C0-C4-alkylene-R3c, O-C0-C4-alkylene-R3c, and C0-C4-alkylene-R3c; R3cis independently selected from C3-C8cycloalkyl, C5-C8cycloalkenyl, phenyl, 3- to 10- membered heterocycloalkyl, 5- to 10-membered heterocycloalkenyl and 5-, or 6-membered heteroaryl; wherein where R3cis cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, R3cis optionally substituted with from 1 to 4 R9groups; and where R3cis phenyl or heteroaryl, R3cis optionally substituted with from 1 to 5 R10groups; R4is independently selected from H, halo, cyano, NR7bR8, OR7, SR7, SOR7, S(O)2R7, S(O)2NR7R7, CO2R7, C(O)R7, C(O)NR7R7, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4- haloalkyl, O-C0-C4-alkylene-R4c, and C0-C4-alkylene-R4c; R4cis independently selected from C3-C8cycloalkyl, C5-C8cycloalkenyl, 3- to 10-membered heterocycloalkyl, 5- to 10-membered heterocycloalkenyl and 5-membered heteroaryl; wherein where R4cis cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, R4cis optionally substituted with from 1 to 4 R9groups; and where R4cis heteroaryl, R4cis optionally substituted with from 1 to 5 R10groups; R5is independently selected from H, halo, cyano, C1-C4-alkylene-NR7R8, NR7bR8, C1-C4- alkylene-OR7, OR7b, SR7, SOR7, S(O)2R7, S(O)2NR7R7, CO2R7, C(O)R7, C(O)NR7R7, C1-C4- alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, NR7-C0-C4-alkylene-R5c, O-C0-C4- alkylene-R5c, and C0-C4-alkylene-R5c; R5cis independently selected from C3-C8cycloalkyl, C5-C8 cycloalkenyl, phenyl, 3- to 10- membered heterocycloalkyl, 5- to 10-membered heterocycloalkenyl and 5-, or 6-membered heteroaryl; wherein where R5cis cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, R5cis optionally substituted with from 1 to 4 R9groups; and where R5cis phenyl or heteroaryl, R5cis optionally substituted with from 1 to 5 R10groups; or R3and R4together with the carbon atoms to which they are attached form a ring selected from: phenyl, C5-C7-cycloalkyl, 5- to 7-membered heterocycloalkyl and 5- or 6- membered heteroaryl; wherein where the ring is cycloalkyl or heterocycloalkyl, it is optionally substituted with from 1 to 6 R9groups and where the ring is phenyl or heteroaryl, it is optionally substituted with from 1 to 4 R10groups; or R4and R5together with the carbon atoms to which they are attached form a ring selected from: phenyl, C5-C7-cycloalkyl, 5- to 7-membered heterocycloalkyl and 5- or 6- membered heteroaryl; wherein where the ring is cycloalkyl or heterocycloalkyl, it is optionallysubstituted with from 1 to 6 R9groups and where the ring is phenyl or heteroaryl, it is optionally substituted with from 1 to 4 R10groups; R6is independently selected from H, halo, C1-C6-alkyl, and C1-C6-haloalkyl; R7and R7aare each independently at each occurrence selected from H and C1-C4alkyl; R7bis independently at each occurrence selected from C1-C4alkyl; R8is independently at each occurrence selected from H, C1-C4alkyl, C1-C4-haloalkyl and C(O)-C1-C4-alkyl R8ais independently at each occurrence selected from H, C1-C4alkyl, C1-C4-haloalkyl, C(O)- C1-C4-alkyl and phenyl optionally substituted with from 1 to 5 R10groups; or R7aand R8a, together with the nitrogen atom to which they are attached, form a 5- to 8-membered heterocycloalkyl ring; optionally substituted with 1 to 4 R9groups; R9is independently at each occurrence selected from =O, =S, halo, nitro, cyano, NR7R8, OR7, SR7, SOR7, S(O)2R7, SO2NR7R7, CO2R7, C(O)R7, CONR7R7, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C1-C3-alkylene-OR7, and C1-C3-alkylene-NR7R8; R9ais independently at each occurrence selected from C3-C8cycloalkyl, C5-C8 cycloalkenyl, phenyl, 3- to 8-membered heterocycloalkyl, 5- to 8-membered heterocycloalkenyl and 5-, or 6-membered heteroaryl; wherein where R9ais cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, R9ais optionally substituted with from 1 to 4 R9groups; and where R9ais phenyl, or heteroaryl, R9ais optionally substituted with from 1 to 5 R10groups; R10is independently at each occurrence selected from halo, nitro, cyano, NR7R8, OR7, SR7, SOR7, S(O)2R7, SO2NR7R7, CO2R7, C(O)R7, CONR7R7, C1-C4-alkyl, C2-C4-alkenyl, C2-C4- alkynyl, C1-C4-haloalkyl, C3-C6-cycloalkyl, C1-C3-alkylene-NR7R8, and C1-C3-alkylene-OR7; and wherein any of the aforementioned alkyl, alkylene, alkenyl, or cycloalkyl groups is optionally substituted, where chemically possible, by 1 to 5 substituents which are each independently at each occurrence selected from the group consisting of: C1-C4-alkyl, oxo, halo, nitro, cyano, NRaRb, ORa, SRa, CO2Ra, C(O)Ra, CONRaRa, S(O)Ra, and S(O)2Ra; wherein Rais independently at each occurrence selected from H, and C1-C4-alkyl; and Rbis independently at each occurrence selected from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and S(O)2-C1-C4-alkyl.

2. A compound according to claim 1, wherein X is N.

3. A compound according to claim 1 or claim 2, wherein R2aand R2bare each H.

4. A compound according to any one of claims 1 to 3, wherein R1comprises at least one amine nitrogen.

5. A compound according to any one of claims 1 to 4, wherein R1is C0-C6-alkylene-R1a.

6. A compound according to claim 5, wherein R1is R1a.

7. A compound according to claim 5 or claim 6, wherein R1ais a 3- to 10-membered heterocycloalkyl group having a nitrogen in the ring system, wherein R1ais optionally substituted with from 1 to 6 R9groups.

8. A compound according to any one of claims 1 to 7, wherein R3is H.

9. A compound according to any one of claims 1 to 7, wherein R3is C1-C4-alkyl.

10. A compound according to any one of claims 1 to 9, wherein R4is H.

11. A compound according to any one of claims 1 to 9, wherein R4is C1-C4-alkyl.

12. A compound according to any one of claims 1 to 11, wherein R5is R5c.

13. A compound according to any one of claims 1 to 12, wherein R5cis phenyl optionally substituted with from 1 to 5 R10groups.

14. A compound according to any one of claims 1 to 12, wherein R5cis 6-membered heteroaryl optionally substituted with from 1 to 5 R10groups.

15. A compound according to any one of claims 1 to 11, wherein R5is H.

16. A compound according to any one of claims 1 to 11, wherein R5is C1-C4-alkyl.

17. A compound according to any one of claims 1 to 9, wherein R4and R5together with the carbon atoms to which they are attached form a C5-C7-cycloalkyl ring; optionally wherein the ring is substituted with from 1 to 6 R9groups.

18. A compound according to claim 1, wherein the compound of formula (I) is selected from:, , ,,19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18, and one or more pharmaceutically acceptable excipients.

20. A compound according to any one of claims 1 to 18, or a pharmaceutical composition according to claim 19, for use as a medicament.

21. A compound according to any one of claims 1 to 18, or a pharmaceutical composition according to claim 19, for use in the treatment of: a disease of the musculoskeletal system, a disease of the skin, a metabolic disease, a disease of the Nervous System, a Cardiovascular disease, an Endocrine disorder, a disease of the eye, a disease affecting the urogenital system, a haemic or lymphatic condition, a respiratory disease, an inflammatory or autoimmune condition, a disease of the Gastrointestinal system, a Neoplasm, cancer, or a disease or disorder selected from Amelogenesis Imperfecta, Anodontia, Odontodysplasia, Branchio-Oto-Renal Syndrome, Sotos Syndrome, and Waardenburg's Syndrome.

22. A compound according to any one of claims 1 to 18, or a pharmaceutical composition according to claim 19, for use in the treatment of a disease selected from: Recessive dystrophic epidermolysis bullosa, Junctional epidermolysis bullosa, Xeroderma pigmentosum, Netherton syndrome, Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, Cystic Fibrosis, Dravet Syndrome, Aniridia, Methylmalonic Acidemia, Colorectal Cancer, Endometrium Cancer, Breast Cancer, Ovarian Cancer, Lung Squamous Cell Carcinoma, Head and Neck Squamous Cell Carcinoma, Familial adenomatous polyposis, Hemophilia A, Hemophilia B, Choroideremia, Pulmonary Artery Hypertension, Ataxia telangiectasia, Shwachman-Diamond syndrome, Mucopolysaccharidosis Type I, Mucopolysaccharidosis Type VI,Mucopolysaccharidosis type III, Niemann-Pick Disease, Primary Ciliary Dyskinesia, Usher syndrome and Retinitis Pigmentosa.

23. A compound according to any one of claims 1 to 18, or a pharmaceutical composition according to claim 19, for use in a method of treating conditions or disorders which are associated with a PTC mutation in a subject.

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